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Expert Opinion on Therapeutic Patents
ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/ietp20
JAK3 inhibitors for the treatment of inflammatory
and autoimmune diseases: a patent review
(2016–present)
Chengjuan Chen, Dianxiang Lu, Tao Sun & Tiantai Zhang
To cite this article: Chengjuan Chen, Dianxiang Lu, Tao Sun & Tiantai Zhang (2022):
JAK3 inhibitors for the treatment of inflammatory and autoimmune diseases: a patent review
(2016–present), Expert Opinion on Therapeutic Patents, DOI: 10.1080/13543776.2022.2023129
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REVIEW
JAK3 inhibitors for the treatment of inflammatory and autoimmune diseases:
a patent review (2016–present)
Chengjuan Chen
a
*, Dianxiang Lu
b
*, Tao Sun
c
and Tiantai Zhang
a
a
State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical
Sciences & Peking Union Medical College, Beijing, China;
b
Research Center for High Altitude Medicine, Key Laboratory of Ministry of Education for
High Altitude Medicine, Qinghai University, Xining, Qinghai, China;
c
Department of Cardiology, Huashan Hospital, Fudan University, Shanghai,
China
ABSTRACT
Introduction: Up to now, a total of eight Janus kinase (JAK) inhibitors have been approved for the
treatment of autoimmune and myeloproliferative disease. The JAK family belongs to the non-receptor
tyrosine kinase family, consisting of JAK1, JAK2, JAK3, and Tyk2. Among these four subtypes, only JAK3
is mainly expressed in hematopoietic tissue cells and is exclusively associated with the cytokines shared
in the common gamma-chain receptor subunit. Due to its specific tissue distribution and functional
characteristics that distinguish it from the other JAKs family subtypes, JAK3 is a promising target for the
treatment of autoimmune disease.
Areas covered: This study aimed to provide a comprehensive review of the available patent literature
on JAK-family inhibitors published from 2016 to the present. In addition, an overview of the clinical
activities of selective JAK3 inhibitors in recent years was provided.
Expert opinion: To date, no selective JAK3 inhibitors have been approved for use in clinics. Over the
last 5 years, an increasing number of studies on JAK3 inhibitors, particularly ritlecitinib by Pfizer, have
demonstrated their promising therapeutic potential. In this review, recent studies reported that selec-
tive JAK3 inhibitors may offer valid, interesting, and promising therapeutic potential in inflammatory
and autoimmune diseases.
ARTICLE HISTORY
Received 10 August 2021
Accepted 22 December 2021
KEYWORDS
Janus kinase; JAK3 subtype;
JAK3 inhibitor; autoimmune
disease; patent review
1. Introduction
The Janus kinases (JAKs) family, which includes JAK1,
JAK2, JAK3, and tyrosine kinase 2 (Tyk2), are intracellular
non-receptor tyrosine kinases that play a key role in deli-
vering cytokine signals from membrane receptors to the
nucleus for transcriptional regulation by signal transducers
and activators of transcription (STAT) [1]. There are over
50 cytokines in mammals, including interleukins, interfer-
ons, and colony-stimulating factors, that exert their effects
through the JAK-STAT signaling pathway. Therefore, JAKs
are critical regulators of cytokine pathways and an attrac-
tive target for the development of anti-inflammatory
drugs in both autoimmune and inflammatory diseases, as
well as myeloproliferative diseases [2].
JAKs have seven distinct Janus homology domain 1–7
(JH1-7) regions and contain approximately 1150 amino
acid residues with about 120–130 kDa molecular weights
[3]. JAK3 has a cysteine residue at position 909 (Cys909) in
its amino acid sequence, which is replaced by a serine
residue at the same position in the other three JAK iso-
forms [4]. In addition to JAK3, only 10 other kinases
possess a Cys909 residue in the ATP-binding site, and
most covalent inhibition strategies target Cys909 to
design selective inhibitor [5]. In contrast to the ubiquitous
expression of the other three JAK family members, JAK3 is
predominantly expressed in hematopoietic tissue cells,
such as NK cells, bone marrow cells, activated
B lymphocytes, and T lymphocytes. The leukocyte-specific
JAK3 was uniquely associated with a shared receptor sub-
unit of the common gamma chain (γc) for IL-2, IL-4, IL-7,
IL-9, IL-15, and IL-21, which regulate the growth and
maturation of NK cells, B cells, and T cells [6]. The loss-of-
function mutations of JAK3 caused severe combined
immunodeficiency syndrome (SCID) [7], which further sup-
ported the importance of JAK3 in the immune system.
Based on the structural and functional characteristics of
the four JAK family subtypes, as well as specific tissue
distribution, JAK3 has emerged as an ideal target for the
treatment of inflammatory or autoimmune diseases [8].
Given the potential of JAK3 as a target, this study aimed
to review the patents on small-molecule JAK3 inhibitors
from 2016 to the present, as well as providing
CONTACT Tao Sun 071105190@fudan.edu.cn Department of Cardiology, Huashan Hospital, Fudan University, Shanghai 200040; Tiantai Zhang
ttzhang@imm.ac.cn State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical
Sciences & Peking Union Medical College, Beijing 100050, China: ao
*
Those authors contributed equally.
Supplemental data for this article can be accessed here.
EXPERT OPINION ON THERAPEUTIC PATENTS
https://doi.org/10.1080/13543776.2022.2023129
© 2022 Informa UK Limited, trading as Taylor & Francis Group
a structured feature analysis of scaffolds in those patents
and the related examples. The clinical activities of selective
JAK3 inhibitors are also briefly described in this review.
2. Recent clinical advances of JAK3 inhibitors
The updated information for approved JAKs inhibitors
(Table 1) and clinical trials of JAK3 inhibitors are described in
this section. The chemical structures of JAK inhibitors that
have been approved and those still in clinical development
are displayed in Figure 1. The status of JAK3 inhibitors in
clinical trials is shown in Table 2.
2.1. Approved JAK inhibitors
Previous studies have proven that the acquired expression or
mutation of JAK kinases is related to many autoimmune dis-
eases and cancers [9–11]. In theory, inhibiting JAK activity to
alleviate or even cure related diseases has become a popular
therapeutic option [12]. JAKs have been shown to be effective
therapeutic targets and there are currently eight JAK inhibitors
that have been approved for the market in the past 10
years [13].
Ruxolitinib (Jakafi®) is a JAK1 and JAK2 dual inhibitor devel-
oped by Incyte/Novartis for the treatment of myelofibrosis
(MF), polycythemia vera (PV), essential thrombocythemia (ET),
and graft-versus-host diseases (GVHD) [14,15]. Tofacitinib
(Xeljanz®) is a pan-JAK inhibitor developed by Pfizer for the
treatment of patients with moderate-to-severe rheumatoid
arthritis (RA), psoriatic arthritis (PsA), ulcerative colitis (UC),
juvenile idiopathic arthritis (JIA), and systemic juvenile idio-
pathic arthritis (SJIA) [16,17]. Baricitinib (Olumiant®) is a JAK1
and JAK2 dual inhibitor developed by Eli Lilly/Incyte for the
treatment of RA, atopic dermatitis (AD), and COVID-19 [18].
Peficitinib (Smyraf®) is a pan-JAK inhibitor developed by
Astellas Pharma for the treatment of RA [19]. Fedratinib
(Inrebic®) is a JAK2 inhibitor developed by Celgene for the
treatment of MF [20]. Upadacitinib (Rinvoq®) is a JAK1 inhibi-
tor developed by AbbVie for the treatment of RA, psoriatic
arthritis (PsA) and ankylosing spondylitis (AS) [21,22].
Delgocitinib (Corectim®) is a pan-JAK inhibitor developed by
Japan Tobacco and Torii Pharmaceutical for the treatment
of AD [23,24]. Filgotinib (Jyseleca®) is a JAK1 and JAK2 inhi-
bitor developed by Gilead for the treatment of RA [24].
2.2. JAK3 inhibitor in clinical development
JAK3 signaling is important for regulating the development,
maintenance, and function of lymphocytes due to its exclusive
association with the γc-containing cytokines receptor unit. As
a result, JAK3 has become a popular target for the treatment
of inflammatory and autoimmune diseases [25,26]. Currently,
several JAK3 inhibitors are being evaluated in clinical trials for
various therapeutic indications.
2.2.1. Ritlecitinib
Ritlecitinib, also known as PF-06651600 developed by Pfizer, is
an orally bioavailable and potent small molecule JAK3-
selective inhibitor with an IC
50
value of 33.1 nM at 1 mM
ATP concentration for JAK3 in biochemical assay and more
than 300-fold selectivity for JAK3 subtype than other subtypes
[27]. It irreversibly inhibits the common γc-related cytokine
signaling dependent on JAK3 by covalently acting on Cys909
residue in the catalytic domain of JAK3 [28]. Ritlecitinib now
was confirmed a dual JAK3/TEC family kinase inhibitor that
displays obviously therapeutic effects on autoimmune disease
such as rheumatoid arthritis (RA), inflammatory bowel disease,
alopecia areata (AA), and vitiligo, by inhibiting Th1 and Th17
cell differentiation and function via JAK3 kinase, and cytotoxic
Table 1. Approved JAK inhibitors and their current indications (Organized alphabetically by compound name, update to 2021.06).
No. Compound Target R&D company Indication
1 Baricitinib JAK1/JAK2 Incyte/Eli Lilly RA, AD, COVID-19 (EUA)
2 Delgocitinib pan-JAK Japan Tobacco AD (approved in Japan)
3 Fedratinib JAK2/FLT3/RET Impact Biomedicines MF
4 Filgotinib JAK1 Gilead, Galapagos NV RA (approved in EU, Japan)
5 Peficitinib pan-JAK Astellas Pharma RA (approved in Japan, South Korea)
6 Ruxolitinib JAK1/JAK2 Incyte/Novartis MF, PV, ET, GVHD
7 Tofacitinib JAK3/JAK1/JAK2 Pfizer RA, PsA, JIA, SJIA, UC
8 Upadacitinib JAK1 AbbVie RA, PsA (approved in EU), AS (approved in EU)
Abbreviations: AD, atopic dermatitis; AS, ankylosing spondylitis; EUA, Emergency Use Authorization; FLT3, fms related tyrosine kinase 3; GVHD, graft-versus-host
disease; JIA, juvenile idiopathic arthritis; MF, myelofibrosis; PV, polycythemia vera; ET, essential thrombocythemia; PsA, psoriatic arthritis; RA, rheumatoid arthritis;
RET, ret proto-oncogene; SJIA, systemic juvenile idiopathic arthritis
Article Highlights
●JAK3 differs from other JAK family subtypes in its cytokine signaling
specificity. In contrast to the ubiquitous expression of other JAKs,
JAK3 is predominantly expressed in the hematopoietic system. In
addition, JAK3 uniquely binds to only one cytokine receptor, the
common gamma chain.
●In principle, restricted expression and function within the hemato-
poietic compartment of JAK3 should result in very limited side effects
on other organs. Thus, selective inhibition of JAK3 should have
a better risk-benefit ratio and higher efficacy in autoimmune disorders
where lymphocyte differentiation is the driving factor.
●The design of compounds based on difference of the active site
Cys909 residues between JAK3 and other JAK subtypes should theo-
retically lead to JAK3 inhibitors that are more selective than other JAK
subtypes.
●Therapeutic opportunities for targeting selective inhibition of JAK3
include, but are not limited to rheumatoid arthritis, inflammatory
bowel disease, cancer, diabetes as well as skin-related diseases such
as alopecia areata, psoriasis, and systemic lupus erythematosus.
●Given that the JAK3 subtype is only responsible for the function of
γc-associated cytokines, selective JAK3 inhibitor has the potential to
overcome clinically occurring side effects by pan-JAKs inhibitors, such
as severe infection, thrombosis and anemia.
2C. CHEN ET AL.
function of NK cells and CD8
+
T cells via TEC kinase [29].
Ritlecitinib has been evaluated in several human phase 1–3
clinical studies due to its favorable efficacy and safety profile.
In 2018, the indication of ritlecitinib for the treatment of AA
was recognized as breakthrough therapy by FDA, and a phase
3 clinical trial is currently evaluating the safety and efficacy of
ritlecitinib in adults and adolescents (12 years and older) with
AA or scalp hair loss of 50% or more (clinicaltrial.gov registry
number: NCT04006457 and NCT03732807).
In 2020, a phase 2a clinical study of patients with mod-
erate-to-severe RA (NCT02969044) showed that oral ritleciti-
nib treatment reduced RA disease activity and generally
well-tolerated over 8 weeks [30]. In this clinical trial, the
incidence of treatment-emergent adverse events (TEAEs)
was higher in the ritlecitinib group (47.6%) than in the
placebo group (17.9), but no serious TEAEs, severe TEAEs,
or deaths were reported. Meanwhile, no bleeding events,
reductions in platelet counts < 100 × 10
3
/mm
3
, or clinically
significant symptoms of anemia or hemodynamic compro-
mise were reported [30]. Another completed phase 2a clin-
ical trial in patients with AA (NCT02974868) showed that
treatment with ritlecitinib for 24 weeks resulted in clinically
significant hair regrowth in patients who have AA with ≥
50% scalp hair loss [31]. There was a significant difference of
Figure 1. (A) The currently approved JAK inhibitors (organized based on approved time). (B) JAK3 inhibitors that are currently in clinical development.
EXPERT OPINION ON THERAPEUTIC PATENTS 3
25% patients between ritlecitinib and placebo groups. The
incidence of adverse events reported in this trial was 74%
and 67% of patients in the placebo and ritlecitinib groups,
respectively. In ritlecitinib treatment group, there was no
clinically relevant change from baseline in hematology
tests, electrocardiogram findings, or vital signs [31]. Based
on above two clinical trials, the most frequently reported
side-effects of ritlecitinib were influenza, pruritus, nasophar-
yngitis, headache, acne, and nausea, but only influenza
(7.1% in the ritlecitinib group and 0% in the placebo
group) and pruritus (4.8% in the ritlecitinib group and 3.6%
in the placebo group) showed the difference compared with
the placebo group.
Now, several human clinical studies of ritlecitinib including
the treatment of Crohn’s Disease (NCT03395184), Ulcerative
colitis (NCT02958865), and vitiligo (NCT03715829) are cur-
rently underway.
2.2.2. ATI-1777
ATI-1777, developed by Aclaris Therapeutics, is an investiga-
tional topical ‘soft’ JAK1/3 inhibitor that is designed to
provide JAK inhibition at the site of application while limit-
ing systemic exposure. A phase 2a, multicenter, randomized,
double-blind, vehicle-controlled, parallel-group clinical trial
to determine the efficacy, safety, tolerability and pharmaco-
kinetics of ATI-1777 in subjects with moderate-to-severe AD
(NCT04598269). Subjects will apply ATI-1777 topical solution
2.0% (w/w) or vehicle twice daily for 4 weeks to explore
whether a topical JAK inhibitor can successfully treat mod-
erate-to-severe AD rather than mild disease [32]. In
Jun 2021, Aclaris Therapeutics announced that the trial
achieved positive results of ATI-1777 in subjects with mod-
erate-to-severe AD with minimal systemic exposure to drug.
The full analysis showed that the trial received its primary
endpoint with a high degree of statistical significance
(p < 0.001) (one-sided p-value), which corresponded to
a 74.4% reduction in modified Eczema Area and Severity
Index (mEASI) score from baseline at week 4 in subjects
applying ATI-1777 compared to a 41.4% reduction in sub-
jects applying vehicle [33]. The topical application for
patients with moderate-to-severe atopic dermatitis is parti-
cularly relevant in light of some of the potential safety
concerns with oral therapies.
2.2.3. TD-5202
TD-5202 is an investigational, gut-selective JAK3 inhibitor devel-
oped by Theravance Biopharma for the treatment of inflammatory
bowel diseases. TD-5202 targets Cys909 residue of JAK3 to conduct
irreversible inhibition. A phase 1, randomized, double-blinded,
placebo-controlled, trial of TD-5202 in healthy volunteers is com-
pleted on 14 January 2021 (NCT04044339) [34].
2.2.4. Decernotinib
Decernotinib, also known as VX-509, is an oral selective JAK3
inhibitor developed by Vertex Pharmaceuticals. It potently
inhibits the JAK3 kinase domain in enzyme assay with Ki
value of 2.5 nM, the potency is about fourfold for JAK3 versus
other three JAK isoforms (JAK1, JAK2, Tyk2). In cell-based
assays, the selectivity of decernotinib is more than 20-fold
for JAK3 over other JAKs subtype [35]. A 12-week phase 2a
clinical trial (NCT01052194) showed that decernotinib was
efficacious in improving clinical signs and symptoms of RA at
dosages of 50–150 mg twice a day as monotherapy in patients
with inadequate response to methotrexate [36]. Another
phase 2b clinical trial (NCT2011-004419-22) reported that
decernotinib significantly improved the signs and symptoms
of RA at weeks 12 and 24 compared with the placebo group
when it was administered in combination with methotrexate
[37]. The current development of decernotinib is presumed to
have been discontinued.
3. Patent assessment of JAK3 inhibitors
3.1. Organization of the review
Patent applications involving JAK inhibitors that were pub-
lished from 2010 to 2015 [38,39] and selective TYK2 inhibitors
that were published in 2019 have been included in a previous
review [40]. Apart from these clinical candidates, additional
structures have been reported in recent scientific publications
and patents. This study focused on publicly available structural
information for patented JAK3 inhibitors, from 2016 to 2021
(1 June 2021). Data from peer-reviewed literature and public
information disclosed by companies were included, where
relevant. Only patents that have been published as WIPO
applications were selected in this study, which was organized
alphabetically by assignee name. Furthermore, a summary and
Table 2. The development status of JAK3 inhibitors in clinic.
No. Compound Target Status R&D company Clinical focus
1 Izencitinib pan-JAK Phase 3 Theravance Biopharma Ulcerative colitis
2 Ritlecitinib JAK3/TEC Phase 3 Pfizer Atopic dermatitis, Vitiligo
3 ATI-1777 JAK1/ JAK3 Phase 2 Aclaris Therapeutics Atopic dermatitis
4 Nezulcitinib JAK1/ JAK2/JAK3 Phase 2 Theravance Biopharma Acute lung injury, COVID-19 complications, Cytokine release
syndrome
5 Ost-122 JAK3/ Tyk2/ NUAK family
kinase 1
Phase 2 Oncostellae Ulcerative colitis
6 Td-8236 pan-JAK Phase 2 Theravance Biopharma Asthma
7 CS-12192 JAK1/ JAK3/ TAK1 Phase 1 Shenzhen Chipscreen
Biosciences
Rheumatoid arthritis
8 R-256 JAK1/ JAK3 Phase 1 Rigel Asthma
9 TD-5202 JAK 3 Phase 1 Theravance Biopharma inflammatory bowel disease
10 Decernotinib JAK3 Discontinued Vertex Pharmaceuticals Rheumatoid arthritis
4C. CHEN ET AL.
analysis including relevant SAR information for the most
potent inhibitors were included.
3.2. Selective JAK3 inhibitors
The selectivity of selective JAK3 inhibitors against other JAK
family subtypes (such as JAK2) is crucial for minimizing potential
side effects and maximizing the desired pharmacological effects.
3.2.1. Aclaris therapeutics
Aclaris Therapeutics disclosed four N-(3-(quinoxalin-2-yl) phenyl)
acrylamide compounds and pharmaceutically acceptable salts
thereof as selective JAK3 inhibitors to be used in the treatment
of JAK3-associated diseases in patent WO2017091681A1 [41].
Compounds14 (Figure 2) all potently inhibit the JAK3 kinase activ-
ity with IC
50
values of 13–18 nM, and their JAK3 selectivity is greater
than 5000-fold than JAK1, JAK2, or TYK2 in biochemical assays.
Compound 2, in particular, is also highly and consistently soluble at
pH 7.4. The compounds also display favorable safety profiles based
on AMES, hERG, and cytotoxicity testing. The in vivo activity of the
compounds 1–4 were investigated in anagen induction hair
growth mode and AA prevention model. The anagen induction
model was used in telogen mouse skin to test the ability of
compounds 1–4 to induce the hair cycle. The results indicated
that Darkening of the skin was observed after approximately 14–
18 days with eruption of new anagen hairs at approximately
28 days after treating with 30 μL 2% of the four different com-
pounds. For prevention of AA in the graft model, C3h/HeJ mice
were grafted with skin from an AA-affected mouse. The tested
JAK3 inhibitors or control was administrated by i.p. injection
(0.5 mg in 50 μL ethylene glycol) daily for 8 weeks. After 6 weeks,
the control treated mice lost their hair as expected in the AA
model. In contrast, the three tested compounds treated mice all
retained their hair.
Figure 2. (A) JAK3 inhibitors from Aclaris Therapeutics. (B) JAK3 inhibitors developed by CAMS and CPU.
EXPERT OPINION ON THERAPEUTIC PATENTS 5
3.2.2. CAMS and China Pharmaceutical University
Chinese Academy of Medical Sciences (CAMS) and China
Pharmaceutical University (CPU) described 28 examples of pyr-
azolo[3,4-d] pyrimidines in the patent WO2020052489 [42]. The
authors designed and synthesized selective JAK3 inhibitors
based on the structural differences between JAK3 subtype with
a cysteine residue at position 909 and other JAK subtypes with
a serine residue at kinase domain. The biochemical inhibitions of
JAKs were provided for all examples. Many of the analogs were
selective JAK3 inhibitors with IC
50
values of less than 1 nM
(compounds 5–8, see Figure 2). Compound 1 irreversibly binds
to Cys909 residue with a potent activity (IC
50
= 0.1 nM) for JAK3
and over 13,000-fold selectivity than other three JAK subtypes. In
vivo, compound 1 was evaluated in an adjuvant-induced arthritis
(AIA) model. Example 1 exhibited dose-dependent effects at 50
and 100 mg/kg, with tofacitinib as a positive control drug [43].
3.2.3. Pfizer
Prior to 2016, Pfizer researchers modified the non-covalent
pan-JAK inhibitor tofacitinib with the aim of converting it
into a covalent inhibitor [27]. JAK3-selective pyrrolopyrimi-
dines and pyrrolopyrazines were substituted with an acry-
lamide moiety as described in the patent WO2015083028
[44]. Example 5, ritlecitinib was identified as the first orally
active JAK3 inhibitors that achieved JAK isoform specificity
through a covalent interaction with the unique JAK3 residue
Cys909 (Figure 3(a)). Pfizer researchers then performed
further studies on this class of irreversible inhibitors.
Another library of pyrrolo[2,3-d] pyrimidine derivatives was
patented in WO2016178110 [45], the majority of which had
an N-1-acryloylpiperidin-3-yl-amino function on C4, analo-
gously to the previous generation of compounds (Figure 3
(b)). Two of the most active compounds on JAK3 were
compounds 9 and 10, with an IC
50
value of 25 nM or
16 nM at 1 mM ATP concentration. The stability of both
these JAK3 covalent inhibitors in rat and human whole
blood was determined. The compounds were tested for
their ability to inhibit IL-15 induced STAT5 phosphorylation
in peripheral blood mononuclear cells and heparin-treated
human whole blood.
Figure 3. (A) Comparison data of ritlecitinib to tofacitinib is presented in WO2015083028. (B) JAK3 inhibitors from Pfizer in WO2016178110. (C) Aromatic
heterocyclic JAK3 inhibitors from Shenzhen Chipscreen Biosciences Ltd (ND means no data).
6C. CHEN ET AL.
3.2.4. Shenzhen chipscreen biosciences
Shenzhen Chipscreen Biosciences Ltd. has published 123
examples of aromatic heterocyclic compounds [46]. Some
of the compounds were evaluated for enzymatic inhibitory,
cell proliferation, and regulation of signaling pathways
in vitro. Compounds 11–13 (Figure 3(c)) exhibited a JAK3
IC
50
of < 21 nM and were the only compounds to have
biological effects on a limited panel of 5 kinases (ITK, BLK,
TBK1, FLT1, FLT4). Findings revealed that compounds 11
and 13 exhibited inhibitory effects against TBK1. In addi-
tion, all three compounds had a good level of specific cell-
inhibitory effect on CTLL-2. Examination of intracellular
inhibitory activity indicated that all three compounds had
intracellular selective JAK3 and/or JAK1 inhibitory effects,
which was consistent with the results of in vitro enzyme
evaluation. Although compounds 11–13 showed potent
inhibition of JAK3, the selectivity is about 10-fold for
JAK3 versus for JAK1. Compounds 11 and 12 were active
at 40 mg/kg twice per day in a rat adjuvant-induced arthri-
tis model. Compared to the solvent group, compound 11
could significantly inhibit the degree of arthritis swelling in
rats, and the inhibition rate of each index was greater than
the positive control drug, methotrexate. Compound 11 was
named CS12192 and is reportedly undergoing a phase 1
trial for rheumatoid arthritis [47].
3.2.5. Theravance Biopharma
Theravance Biopharma focuses on the research and devel-
opment of organ selective JAKs inhibitors [48–50].
Approximately 440 examples of pyrazolo and triazolo bicyc-
lic compounds were reported as JAK inhibitors, particularly
as JAK3 inhibitors in enzyme-binding assays, in the patent
WO2019027960 [48]. The disclosed compounds have been
shown to have potent functional activity for JAK3 in cellular
assays by testing IL-2 stimulated pSTAT5 in Tall-1 T cells and
human peripheral blood mononuclear cells (PBMC) CD4
+
T cells. According to the patents, new JAK3 inhibitors that
can be administered orally and achieve therapeutically rele-
vant exposure in the gastrointestinal tract with minimal
systemic exposure were developed. Co-crystal structures
were obtained for compounds 14, 15, and 16 (Figure 4),
with each bound to human JAK3. Twenty compounds,
including compounds 14–16, exhibited an efficacy in oxa-
zolone-induced colitis animals at a dose of 3 mg/kg (p.o.,
bid). A murine model with IL-2 induced pSTAT5 in the
thymus showed that compounds 14–16 did not significantly
inhibit IL-2 induced pSTAT5, indicating these JAK3 inhibitors
have gut-selective property.
In WO2020154350 [50], the invention is directed to imi-
dazole and triazole containing bicyclic compounds as selec-
tive JAK3 inhibitors. In WO2021108803 [49], fused
Figure 4. Pyrazolo and triazolo bicyclic compounds from Theravance Biopharma.
EXPERT OPINION ON THERAPEUTIC PATENTS 7
pyrimidine pyridinone compounds were disclosed to use as
JAK3 inhibitors. The disclosed 316 compounds displayed
potently inhibitory activity for JAK3 in cellular assays of IL-
2 stimulated pSTAT5 in Tall-1 T cells and human PBMC CD4
+
T cells. In CellTiter-Glo luminescent cell cytotoxicity assay,
the test compounds had less likelihood to cause cytotoxi-
city. The compounds 17–21 (Figure 4) exhibited
a statistically significant decrease in combined stool score
endpoint as compared with vehicle treated animals in the
oxazolone-induced colitis model at a dose of 1 mg/kg (p.
o., bid).
3.3. Nonselective JAK3 inhibitors
This section describes recently patented JAK3 inhibitors that
exhibit some degree of activity against other JAK family mem-
bers. The content was classified by patents application.
3.3.1. Boragen Inc
Boragen Inc has developed several chemical compounds as
JAK inhibitors [51]. Most of the compounds described in this
patent appear to be active against JAK1 and JAK2. But accord-
ing to the provided JAK enzyme data, compounds 22, 23, and
24 (Figure 5(a)) also displayed potent inhibition activity for
JAK3 with IC
50
value of 0.66 nM, 1.2 nM, and 0.29 nM, respec-
tively. The cellular assay also showed that 21, 22 and 23
obviously inhibited the expression of the pSTAT6 induced by
IL-4 in peripheral blood mononuclear cell and the pSTAT5
induced by GM-CSF in human whole blood.
3.3.2. Celon pharma
Celon Pharma has developed novel pyrazolo[1,5-a] pyrimi-
dine derivatives with more potent JAK1/JAK3 kinases inhibi-
tion than kinase JAK2 inhibition (compounds 25–27, Figure 5
(b)) [52]. Cellular assays using IL-3 (JAK2 activation) or IL-4
(JAK1/JAK3 activation) stimulation of TF-1 cells were con-
ducted to measure the inhibition of cell viability.
Furthermore, assays for TNF-α inhibition and IFN-γ produc-
tion by T lymphocytes were described. Compounds 25, 26,
and 27 were also reported to inhibit in vitro STAT6
phosphorylation.
Figure 5. (A) JAK inhibitors from Boragen Inc. (B) JAK inhibitors from Celon Pharma in patent WO2018206739. (C) Pyrrolopyrimidine five-membered azacyclic from
Huadong Medicine Co., Ltd.
8C. CHEN ET AL.
3.3.3. Huadong Medicine Co., Ltd
Huadong Medicine Co., Ltd. developed a pyrrolopyrimidine five-
membered azacyclic derivative as a novel JAK kinase inhibitor
[53]. Only two compounds, 28 and 29 (Figure 5(c)) similar to
barictinib in structure, were published that they inhibited JAK3
with IC
50
of 27 nM and 31 nM, respectively. In the rat AIA model,
compound 28 showed a 100% inhibition rate at 10 mg/kg.
Administration of compounds 28 and 29 once daily at 30 mg/
kg for 14 days was well tolerated in rat toxic side effects tests.
3.3.4. Jiangsu Hansoh Pharmaceutical Group Co., Ltd
Jiangsu Hansoh Pharmaceutical Group Co., Ltd. described 319
examples of heteroaromatic derivatives [54]. Most of the
examples showed that compounds exhibited strong inhibitory
activity against JAK1 and JAK2. Several analogs, compounds
30–35 with a 7–8 membered bridge heterocyclic group, dis-
played in Figure 6(a) were very potent JAK3 inhibitors with
IC
50
values of less than 10 nM. In IFN-α-stimulated cellular
assay, compounds of 30–35 all significantly inhibited the
phosphorylation of STAT3 (with IC
50
from 0.29 to 11.05 nM),
the downstream effector molecule of JAKs. The PK of com-
pounds 30–35 in Balb/c mice was also determined, with
results revealing good exposure levels in the colon and
ileum. In the DSS-induced C57BL/6 mouse colitis model, com-
pounds 30–35 significantly reduced the daily disease index
(DAI) and had obvious drug effects.
Figure 6. (A)Heteroaromatic derivatives from Jiangsu Hansoh Pharmaceutical Group Co Ltd. (B) Heteroaromatic derivatives from Jiangsu Vcare Pharmatech Co Ltd.
EXPERT OPINION ON THERAPEUTIC PATENTS 9
3.3.5. Jiangsu Vcare Pharmatech Co., Ltd
Jiangsu Vcare Pharmatech Co., Ltd. developed 23 com-
pounds with a 7-azaindole core [55]. A minimal amount of
structure–activity relationship (SAR) was conducted at the
C-1 and C-6 positions of pyridine. Data for the biochemical
inhibition of JAKs was published, with most compounds
shown to exhibit IC
50
values of < 10 nM. However, no
cellular data was reported. There were two developed com-
pounds, 36 and 37 (Figure 6(b)), that had significant inhibi-
tory effects in DSS-induced colitis in mice at 5 mg/kg.
Furthermore, both compounds had superior efficacy than
the positive control drug tofacitinib at the same dose. In
addition, compound 37 displayed a significant inhibitory
effect on rat DNBS induced colitis at a lower dose of
1 mg/kg.
3.3.6. Nanchang Helioeast Pharmaceutical Co., Ltd
Nanchang Helioeast Pharmaceutical Co Ltd. has filed two
patents for JAK3 inhibitors. A serious of pyrimidine-amino-
imidazol compounds with a range of substituents at posi-
tion N-1 imidazol and C-4 pyrimidine were described in
patent WO2017020428 (compounds 38–42) [56]. And
4,7-diamino-pyrido[2,3-d] pyrimidine derivative JAK inhibitor
was described in patent WO201788289 (compounds 43–45,
Figure 7) [57]. In vitro enzymatic-level assay, compounds
37–44 were all displayed potent inhibitory activity for
JAK3 with IC
50
of < 20 nM. In cellular assays, compounds
38–45 inhibited STAT5 phosphorylation by IC
50
value in the
200–2000 nM rang in IL-3-induced TF-1 cells. In IL-4-induced
THP-1 cells, they inhibited STAT6 phosphorylation by IC
50
value of < 200 nM. In vivo collagen-induced mouse
Figure 7. JAK family kinase inhibitors from Nanchang Helioeast Pharmaceutical Co Ltd.
10 C. CHEN ET AL.
rheumatoid arthritis (CIA) model assay, the selected com-
pounds were all significantly reduced the clinical inflamma-
tory symptom scores.
3.3.7. Novartis
Novartis developed novel diamino pyridine derivatives exhibit-
ing JAK modulating properties [58]. Only two compounds, 46
and 47 (Figure 8(a)), that inhibited the JAK enzyme were
disclosed. There were no reported cellular and in vivo data.
3.3.8. Shenzhen Amazing Genetech Co., Ltd
Shenzhen Amazing Genetech Co., Ltd. developed 416 pyr-
rolo pyridine derivatives as selective inhibitors of JAK1
[59]. According to the kinase data, several compounds
displayed JAK3 inhibition effects. The majority of the com-
pounds that inhibited JAK3 activity had a pyrrolo substi-
tuent at C-5 pyridine and a range of substituents at C-4
pyridine. The selected activities of the compounds
(Figure 8(b)), including 48, were investigated in a mice
CIA model and exhibited an obvious therapeutic effect
on mouse arthritis. The compounds were added to an
emulsifier to form a 2% ointment, with results showing
that compounds 48 and 49 have obvious hair growth-
promoting effects in mice assay.
3.3.9. Takeda Pharmaceutical Co., Ltd
A patent of Takeda Pharmaceutical Co., Ltd. described hetero-
cyclic compounds as JAK inhibitors [60]. The JAK inhibition
percentages at 100 nM were provided for all 23 examples,
Figure 8. (A) Inhibitors of JAK family kinases from Novartis.(B) Pyrrolo pyridine derivatives from Shenzhen Amazing Genetech Co Ltd. (C) Heterocyclic compounds
from Takeda Pharmaceutical Co Ltd.
EXPERT OPINION ON THERAPEUTIC PATENTS 11
with most compounds exhibiting > 95% inhibition.
Compounds 50–52 (Figure 8(c)) were the more potent exam-
ples of JAK3 inhibitors. There were no reported cellular and
in vivo data.
3.3.10. Theravance Biopharma
3.3.10.1. Gut-selective JAK inhibitor. Theravance
Biopharma has filed several patents for gut-selective JAKs
inhibitors. In 2016, Theravance Biopharma described
naphthyridine compounds as JAKs inhibitors in patent
WO2016191524 [61]. In biochemical assays, compounds 53–
56 displayed Ki values < 100 nM for JAK3 (Figure 9(a)). The oral
bioavailability of compounds 53 and 54 were all less than 5%
in rats, and the concentration of 53 in the colon is 450 times
higher than in the plasma. The results show that these com-
pounds had gut-selective properties. Compounds 52, 53, and
56, also exhibited a significant decrease in DAI score in the
oxazolone model as compared to the vehicle-treated animals
at 1, 3, and/or 10 mg/kg (p.o., bid). There were no effects of
B and T cell populations on the immunosuppressive properties
Figure 9. (A) Gut-selective JAK inhibitors from Theravance Biopharma. (B) Skin-selective JAK inhibitors from Theravance Biopharma.
12 C. CHEN ET AL.
of mouse splenic natural killer (NK) with the treatment of
compound 53 at doses of up to 100 mg/kg (p.o., bid). In
a human study, compound 53 was evaluated for safety, toler-
ability, and PK in healthy subjects. Compound 53 has now
been named TD-1473 or izencitinib, a recent phase 2b, multi-
center, randomized, double-blind, vehicle-controlled, parallel-
group clinical trial in patients with ulcerative colitis showed
that izencitinib had not significant difference at any dose in
the change in total score at week 8 relative to placebo
(NCT03758443) [62]. In patent WO2017189822 [63],
a pyrimidine with heterocyclyl containing 4 to 6 ring atoms,
including one nitrogen atom, was described as a JAKs kinase
inhibitor. The structure of the potent JAK3 inhibitor, com-
pound 57, is shown in Figure 9(a).
3.3.10.2. Skin-selective JAK inhibitor. Theravance
Biopharma has also filed two further patents for compounds
with similar structures to those described in patent
WO2017189822 [63]. The compounds described in both patents
possess advantageous solubility properties in aqueous and/or
organic excipients that facilitate formulation into topical
compositions. There were 10 ester and carbonate pyrimidine
compounds described in patent WO2020219639 [64]. The 46
pyrimidine compounds described in patent WO2020219640
[65] were expected to sustain dermal levels in the absence of
significant systemic levels with potent local anti-inflammatory
and anti-pruritic activity in the skin without systemically driven
adverse effects. Compounds 58–64 (Figure 9(b)) potently inhib-
ited the activity of JAK1/JAK2/JAK3/Tyk2 with Ki value < 1 nM in
biochemical assays. In cellular assays, 58–64 showed significant
inhibitory effect on STAT5 phosphorylation induced by IL-2 with
pIC
50
≥ 8.0. In metabolic stability assay, compound 58 exhibited
an HLM Clint of 132 µL/min/mg, compound 61 exhibited over
2500 µL/min/mg, and compound 62 exhibited 1250–3000 µL/
min/mg in a human liver microsome. As topical skin application
compounds, the PK of the epidermal, dermal, and plasma in the
ointment (0.25%) were determined following 24 hours of topical
exposure to intact male rat skin. Compounds 61 exhibited
a conversion over 30% in this assay.
3.3.10.3. Lung-selective JAK inhibitor. Since 2017,
Theravance Biopharma has claimed a series of fused imidazo-
Figure 10. Lung -selective JAK inhibitors from Theravance Biopharma.
EXPERT OPINION ON THERAPEUTIC PATENTS 13
piperidine compounds with a core structure of indazol-
4,5,6,7-tetrahydro-imidazol-pyridine as JAKs inhibitors for the
treatment of respiratory diseases. In patent WO2017079205
[66], compounds 65–67 (Figure 10) exhibited potent inhibitory
activity against JAK3 with pKi IC
50
≥ 10 nM in biochemical
assay and with pIC
50
≥ 8 nM in cellular assay. In patent
WO2018165392 [67] and WO2018165395 [68], the compounds
were described as having the same core structure as com-
pounds in patent WO2017079205, exemplified by compounds
68–72 as JAKs inhibitors with Ki < 0.25 nM for JAK3 and <
0.1 nM for JAK1.
In 2020, Theravance Biopharma filed patent
WO2020051105 for new series of dimethyl amino azetidine
amides compounds [69]. Compounds 73 and 74 (Figure 11(a))
possessed JAK3 inhibitory activity with pKi IC
50
values of 10.2
and 10.1 nM, respectively. Compound 73 also exhibited good
PK properties in the plasma and lung, as well as good meta-
bolic stability in human lung S9. In human 3D airway cultures
derived from asthmatic donors, compound 73 inhibited spon-
taneous periostin and IL-6 secretion by 62% ± 25 (at 10 mM)
and 91% ± 9.0 (at 10 mM), respectively, when compared to
vehicle. Assays of lung s9 metabolism and PK in mice plasma
and lungs demonstrated that the compounds exhibited expo-
sure in lungs that is one to two orders of magnitude greater
than exposure in plasma in mice. The compounds caused IL-
13 induced pSTAT6 activation and alternata-induced eosino-
philic inflammation of the murine lung tissue. Furthermore,
the compounds inhibited bronchoalveolar lavage fluid
Figure 11. (A) Lung -selective JAK inhibitors from Theravance Biopharma. (B) JAK inhibitors from Topivert Pharma Ltd.
14 C. CHEN ET AL.
eosinophil counts 48 hours after alternaria challenge.
Compound 73, also named as TD-0903 or nezulcitinib, was
performed a phase2 randomized, double-blind, placebo-
controlled clinical trial (NCT04402866) to treat symptomatic
acute lung injury associated with COVID-19 [70]. The com-
pleted clinical trial showed that the study did not meet the
primary endpoint (Respiratory Failure-Free Days, RFDs) from
randomization htrough day 18 in the intent-to-treat (ITT)
population [71]. Although inhaled nezulcitinib had no statis-
tically significant difference in RFDs from randomization
through Day 28 between nezulcitinib and placebo in ITT,
nezulcitinib demonstrated a favorable trend in improvement
when compared to placebo for 28-day all-cause mortality
rate [72].
Patents WO2020051135 [73] and WO2020051139 [74]
claimed 13 compounds and some of their fluorine substituted
compounds o treat respiratory diseases. Compounds 75–77
(Figure 11(a)) possessed JAK3 inhibitory activity with pKi IC
50
values of < 10 nM. In IL-13 induced mouse model, 75–77
significantly inhibited the expression of pSTAT6 in lung tissue.
In mice, the lung-to-plasma ratio at 5 hours revealed that
compounds 75–77 exhibited significantly more exposure in
the lung than in plasma. The potency (pIC
50
) values of com-
pounds 75–77 were all less than 7.5 for the inhibition of
thymic stromal lymphopoietin (TSLP) evoked thymus and acti-
vation-regulated chemokine (TARC) release in hPBMC.
3.3.11. Topivert Pharma Ltd
Topivert Pharma Ltd. has filed two patents on JAKs inhibitors
[75,76]. A total of 47 indazole substituents with similar struc-
tures to the phase I discontinued pan-JAK inhibitor
PF06263276 (compounds 78, Figure 11(b)) were disclosed
[77]. It was surprisingly discovered that compounds bearing
certain aminoheteroaryl substituents inhibited one or more
JAK enzymes, thus possessing good anti-inflammatory
Figure 12. (A) Tricyclic compounds in patent WO2021043850 of Universität Bern. (B) JAK inhibitors from Vimalan Biosciences Inc.
EXPERT OPINION ON THERAPEUTIC PATENTS 15
properties. The chemotype consisted of a central biaryl com-
posed of an indazole and phenyl ring, with the other ring
being tetrahydro imidazole-pyridine. Compounds 79–81
(Figure 11(b)) were all potent JAK3 inhibitors with IC
50
< 0.1 nM. Compound 79 was substantially more potent than
PF06263276 in inhibiting IFN-γ release from CD3/IL2-
stimulated PBMC cells and/or potentially displaying enhanced
viability in the Jurkat cell cytotoxicity assay.
3.3.12. Universität Bern
Universität Bern described two tricyclic compounds of
KMC420 (compound 82) and KMC423 (compound 83,
Figure 12(a)) in patent WO2021043850 [78]. Compound 83
showed potent inhibitory activity against JAK3 with 9 nM of
IC
50
value, and selectivity is 3.5-fold, 6-fold, and 20-fold for
JAK1, JAK2, and Tyk2, respectively. Now, there is no further
information available about this patented compound.
3.3.13. Vimalan Biosciences Inc
Vimalan Biosciences Inc. has published three patents describ-
ing pyrrolo pyrimidin compounds. Much of the peripheral SAR
has remained constant: for example, the pyrimidine is gener-
ally substituted at the C-2 position with an N-pyrazole amide.
The selected compounds 84–90 (Figure 12(b)) were evaluated
for their ability to inhibit JAK3 with IC
50
< 100 Nm. The IL-2
(JAK1/JAK3-dependent) stimulation and measurement of
STAT5 phosphorylation cellular assays were performed on
PBMCs. Meanwhile, GM-CSF (JAK1/Tyk2 or JAK2-dependent)
stimulation and measurement of STAT1/5 phosphorylation
cellular assays were performed in hWBs. However, there were
no reported data in patents WO2021026465 [79] and
WO2020227563 [80]. Cellular data was disclosed for com-
pounds 89 and 90 in patent WO2021062036 [81].
4. Conclusion
Over the past 5 years, many patent applications for JAK3
inhibitors have been filed. In order to avoid the side effects
caused by non-selectivity, selective JAK inhibitors are the
direction of the new generation of JAK inhibitors develop-
ment. Although there are many JAK inhibitors being
approved or in development, no truly selective JAK3 inhibi-
tion is approved and only a few are in preclinical or clinical
development. Ritlecitinib, developed by Pfizer, is under-
going several clinical trials in multiple indications. Recently
completed a phase 2a randomized, placebo-controlled study
to evaluate the efficacy and safety clinical trial for AA
showed that ritlecitinib treatment was efficacious and gen-
erally well tolerated at 24 weeks. TD-5202 also a JAK3-
selective inhibitor was developed by Theravance
Biopharma, an interesting is that it was first designed as
gut-targeted selective JAK3 inhibitor to specially treat
inflammatory bowel disease [34].
5. Expert opinion
In view of the side effects caused by nonselective inhibiting
JAKs in clinic, such as infection, hematological and cardiovas-
cular effects, and malignancies [82,83], there is increasing
research focus on selective JAK inhibitors to overcome these
issues. For four isoforms of JAK kinase, JAK3 is predominantly
expressed in hematopoietic cells against to extensive expres-
sion of other three subtypes. JAK3 possess a unique Cys909
residue at kinase domain, and the residue replaced by a serine
in equivalent position in the other three JAK isoforms. The
specificity of JAK3 isoform made it a potentially ideal target for
discovering selective JAK3 inhibitors [84].
The 909-cysteine residue of JAK3 allows for the develop-
ment of a selective JAK3 inhibitor over other JAK family
members. Compounds containing electrophilic warheads
are capable of forming a covalent bond with the nucleo-
philic thiol of the cysteine residue. However, further studies
are required to understand whether a covalent JAK3 inhibi-
tor can be used as an effective disease treatment. The dual
activity of ritlecitinib against JAK3 and the TEC kinase family
may provide a beneficial inhibitory profile and generally
well tolerated during 24-week therapeutic intervention
[85]. TEC family kinase consists of five members (Bruton’s
tyrosine kinase (BTK), bone marrow tyrosine kinase on chro-
mosome X (BMX), interleukin 2-inducible T cell kinase (ITK),
resting lymphocyte kinase (RLK), and TEC). The TEC kinase
family of tyrosine kinases is primarily expressed in immune
cells, and activated TEC kinase by a variety of signals are
involved in signal transduction pathways regulating various
immunological processes in health [86]. The clinical trials of
ritlecitinib showed positive efficacy on RA and AA, and no
treatment-related serious AEs, severe AEs, or deaths were
reported. The efficacy and safety of JAK3-selective inhibitor
as an ideal target need to be further confirmed by more
clinical trials.
Although the JAK3 subtype has the appeal of a target that
is functionally different from other JAK subtypes, no selective
JAK3 inhibitor has yet been approved for the treatment of
inflammatory and autoimmune diseases. Although further
work is required to understand the specific mechanism by
which JAK3 signaling is inhibited and the therapeutic potential
of targeting JAK3, ongoing clinical and pre-clinical trials of
selective JAK3 inhibitors may provide insight and therapeutic
advantages.
Declaration of interests
The authors have no relevant affiliations or financial involvement with any
organization or entity with a financial interest in or financial conflict with
the subject matter or materials discussed in the manuscript. This includes
employment, consultancies, honoraria, stock ownership or options, expert
testimony, grants or patents received or pending, or royalties.
Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial or other
relationships to disclose.
Funding
This work was supported by the National Natural Science Foundation of
China (81973338, 82104189).
16 C. CHEN ET AL.
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