Zhengying Pan's research while affiliated with Peking University and other places
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Publications (34)
B-lymphoid tyrosine kinase (BLK) is an important knot of B cell receptor signaling, and regulates the function and development of B cells subset. Dysfunction of BLK is correlated with autoimmune diseases and cancer. There is an urgent need to develop selective BLK modulators to facilitate the studies of BLK in biological processes. Herein, we repor...
Interleukin-2-inducible T-cell kinase (ITK) is a promising therapeutic target for human autoimmune diseases and T-cell malignant lymphomas. This paper reports the development of a series of cereblon-recruiting ITK proteolysis targeting chimeras based on a structure-based design strategy. The representative compounds 23 and 28 exhibited potent ITK d...
Mitogen-activated protein kinase kinases 1/2 (MEK1/2) play critical roles in the canonical RAS/RAF/MEK/ERK pathway. Highly selective and potent non-ATP-competitive allosteric MEK1/2 inhibitors have been developed, and three of them were clinically approved for the treatment of BRAFV600 -mutant melanoma. However, the accompanying side effects of the...
Fibroblast growth factor receptor 4 (FGFR4) has been identified as a potential target for the treatment of hepatocellular carcinoma (HCC) with aberrant FGFR4 signaling because of its important role in HCC progression and development. Several FGFR4 inhibitors are under clinical development. Using a 7-azaindole scaffold, we discovered a series of nov...
Although extracellular regulated protein kinases (ERKs) are considered important targets for the treatment of various cancers, the occurrence of severe side effects in clinical trials restricts the development of ERK inhibitors. Here, we developed the first series of photocaged ERK inhibitors, which can be selectively activated by UV irradiation to...
PES (2-phenylethynesulfonamide, pifithrin-μ, PFTμ) is an electrophilic compound that exhibits anticancer properties, protects against chemotherapy-induced peripheral neuropathy in chemotherapy, and shows immunomodulatory, anti-inflammatory and anti-viral activities. PES generally shows higher cytotoxicity towards tumor cells than non-tumor cells. T...
B-lymphoid tyrosine kinase (BLK), a member of the SRC family nonreceptor tyrosine kinase, is involved in the B-cell receptor (BCR) signaling pathway and B cell development and function. Dysregulation of BLK is associated with autoimmune diseases and cancer. However, there is an absence of good tool compounds for BLK, and the molecular mechanisms by...
Covalent inhibitor-based PROTACs were successfully developed for the degradation of target proteins in live cells to further extend the application scope of PROTACs.
Interleukin-2 inducible T-cell kinase (ITK), a member of the Tec family of tyrosine kinases, plays an important role in T cell signaling downstream of the T-cell receptor (TCR). Herein we report the discovery of a series of indolylindazole based covalent ITK inhibitors with nanomolar inhibitory potency against ITK, good kinase selectivity and poten...
Induction of protein degradation is emerging as a powerful strategy to modulate protein functions and alter cellular signaling pathways. Proteolysis-targeting chimeras (PROTACs) have been used to degrade a range of diverse proteins in vitro and in vivo. Here we present a type of photo-caged PROTACs (pc-PROTACs) to induce degradation activity with l...
Interleukin-2-inducible T-cell kinase (Itk) plays an important role in multiple signal transduction pathways in T and mast cells, and is a potential drug target for treating inflammatory diseases, autoimmune diseases, and T cell leukemia/lymphoma. Herein, we describe the discovery of a series of covalent Itk inhibitors based on the 7H-pyrrolo[2,3-d...
Background
Angioimmunoblastic T cell lymphoma (AITL) is a distinct subtype of peripheral T cell lymphoma and associated with poor outcomes. The activation status of T cell receptor (TCR) signaling has recently become a focus of attention in terms of the therapeutic targets. However, the molecular pathogenesis mechanisms and novel therapeutic target...
JAK family kinases are important mediators of immune cell signaling and Janus Kinase 3 (JAK3) has long been indicated as a potential target for autoimmune disorders. Intensive efforts to develop highly selective JAK3 inhibitors have been underway for many years. However, because of JAK3's strong binding preference to adenosine 5′-triphosphate (ATP)...
As an important kinase in multiple signal transduction pathways, GSK-3β has been an attractive target for chemical probe discovery and drug development. Compared to numerous reversible inhibitors that have been developed, covalent inhibitors of GSK-3β are noticeably lacking. Here, we report the discovery of a series of covalent GSK-3β inhibitors by...
As a key regulator of the B-cell receptor signaling pathway, Bruton’s tyrosine kinase (Btk) has emerged as an important therapeutic target for various malignancies and autoimmune disorders. However, data on the expression profiles of Btk are lacking. Here, we report the discovery of a new, selective Btk probe and of a sandwich-type ELISA quantifica...
Fluorophosphonate probes covalently immobilize proteins onto solid support by reacting with tyrosine 111 in the GST tag.
Mantle cell lymphoma (MCL) is an aggressive and incurable malignant disease. Despite of general chemotherapy, relapse and mortality are common, highlighting the need for the development of novel targeted drugs or combination of therapeutic regimens. Recently, several drugs that target the B-cell receptor (BCR) signaling pathway, especially the Brut...
Bruton’s tyrosine kinase has emerged as a promising drug target for multiple diseases, particularly hematopoietic malignancies. As a result of intensive efforts, many inhibitors have been developed to target BTK. Among them, considerable progress has been made in covalent inhibitors. In this chapter, example compounds will be discussed to highlight...
The Bruton's tyrosine kinase (Btk) inhibitor ibrutinib has demonstrated promising efficacy in a variety of hematologic malignancies. However, the precise mechanism of action of the drug remains to be fully elucidated. Tumor-infiltrating macrophages presented in the tumor microenvironment have been shown to promote development and progression of B-c...
This chapter discusses the pharmacology, structure-activity relationship (SAR), pharmacokinetics and drug metabolism, efficacy and safety, and syntheses of ibrutinib. Ibrutinib has received the approvals for the treatment of mantle cell lymphoma (MCL), chronic lymphocytic leukemia (CLL), and Waldenstrom's macroglobulinemia (WM). Ibrutinib is a sele...
As a critical regulator of the B-cell receptor signaling pathway, Bruton’s
tyrosine kinase (Btk) has attracted intensive drug discovery efforts for treating
B-cell lineage cancers and autoimmune disorders. In particular, covalent inhibitors
targeting Cys481 in Btk have demonstrated impressive clinical benefits, and their
companion affinity probes h...
The B-cell receptor (BCR) signaling pathway has gained significant attention as a therapeutic target in B-cell malignancies. Recently, several drugs that target the BCR signaling pathway, especially the Btk inhibitor ibrutinib, have demonstrated notable therapeutic effects in relapsed/refractory patients, which indicates that pharmacological inhibi...
Highly substituted chiral hydantoins were readily synthesized from simple dipeptides in a single step under mild conditions. This reaction proceeded through the dual activation of an amide and a tert-butyloxycarbonyl (Boc) protecting group by Tf2O-pyridine. This method was successfully applied in the preparation of a variety of biologically active...
A general approach is presented for developing small molecule-based fluorogenic probes suitable for no-wash imaging of endogenous kinases in live cells. Probe , including a fluorophore-quencher system, was only "turned on" upon reacting with its target kinase Btk, and disclosed Btk's cellular location in live cells without any washing.
The immobilization of functional proteins onto solid supports using affinity tags is an attractive approach in recent development of protein microarray technologies. Among the commonly used fusion protein tags, glutathione S-transferase (GST) proteins have been indispensable tools for protein-protein interaction studies and have extensive applicati...
Bruton's tyrosine kinase (Btk) is an attractive drug target for treating several B-cell lineage cancers. Ibrutinib is a first-in-class covalent irreversible Btk inhibitor and has demonstrated impressive effects in multiple clinical trials. Herein, we present a series of novel 2,5-diaminopyrimidine covalent irreversible inhibitors of Btk. Compared w...
Glyoxalase I (GLO-1) plays a critical role in the detoxification of 2-oxoaldehydes and is highly expressed in cancer cells. Through photo-affinity labelling and affinity pull-down approaches, a series of 2,4-diaminopyrimidine compounds were discovered to selectively bind to GLO-1 in cells. These compounds show potent inhibition of GLO-1 enzyme acti...
Citations
... Azaindole analogues were reported active as CRTh2 receptor antagonists, [19][20][21][22][23] antioxidant agents, 24 antibacterial agents [25][26][27] and antifungal agents. 28 Azaindole derivatives were also found to be active as Chk1 inhibitors, 29 FGFR-4 inhibitors, 30 PI3Kγ Inhibitors. 31 In present studies there was synthesis of some novel Azaindole analogues which were found to be active as anticancer agent. ...
... [10] It was only in 2012 that this area began to grown gently. [11] Since then, both photopharmacological approaches have been applied on a variety of protein kinase inhibitors targeting RET kinase, [12] protein kinase C, [13] MEK1, [14] VEGFR-2, [15] BRAF V600E , [16] JNK3, [17] PKA, [18] Rho kinase, [11] CKI, [19] ERK1/2, [20] and PIK3. [21] Most interestingly, the group of Peifer developed a photocaged version of two marketed kinase inhibitors, imatinib [22] and vemurafenib. ...
... Furthermore, we developed cysteine-mutated NanoBRET assays for Cys481 for BTK 19 and Cys319 for BLK. 17 As expected, ZNL0325 lost its inhibitory activity in both cell lines ( Figure S5A,B). ...
... Importantly, covalent E3 recruiters cannot be inhibitory of ligase function since this would invalidate their utility in a TPD setting, and thus avoiding reaction with active site residues in ligases that have enzymatic activity is essential. The concept of target-covalent degraders has been explored for BTK, utilizing both reversible and irreversible covalent ibrutinib derivatives [15][16][17]. Since ibrutinib has high non-covalent binding affinity for BTK, covalent degraders based on this ligand will fundamentally be expected to reduce potency due to loss of catalytic function [16]. ...
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... While targeted delivery methods may enhance selectivity, recent advances in the field of opto-PROTACs may afford an alternative method for achieving selectivity through the spatiotemporal control of PROTAC activation ( Figure 3D). These strategies use caging groups or photoswitches that serve to maintain the PROTAC in an inactive state until exposed to light [110,[119][120][121]. Opto-PROTACs have now been used to successfully target several POIs, including ALK, BRD2, BRD3, BRD4, and BTK [110,[119][120][121]. ...
... Moreover, compound 9 showed a 250-fold greater selectivity for ITK over BTK as well as successful inhibition of phosphorylation of PLCγ1. Therefore, compound 9 could be a promising new inhibitor to target ITK [83]. ...
... Thus blocking ITK with BMS-509744 can directly ameliorate multiple features of T cell exhaustion. Liu et al. demonstrated that ITK inhibition monotherapy with BMS-509744 suppressed T cell lymphoma both in vivo and in vitro by downregulating TCR signaling pathway, which is highly activated in malignant T cells 38 . Our data show that ITK treatment alone has no therapeutic effects in solid tumors in vivo, while it directly reinvigorates in vitro exhausted CTLs and increases tumor-specific CD8 + T cells in the tumor draining lymph node. ...
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... Three drugs in Figure 2 shared a common α,β-unsaturated amide moiety to allow the Michael addition to the target protein via covalent binding. A number of JAK3 covalently bound inhibitors have been reported and some have been studied under various stages of clinical trials [19][20][21][22][23][24][25][26][27][28][29]. JAK1, JAK2, and TYK2 are highly expressed in most cell types while JAK3 is mostly expressed in hematopoietic cells [17]. ...
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... These maleimidebased molecules are not PAN-kinase inhibitors but instead only interact with one kinase, Glycogen Synthase Kinase-3 (GSK-3), [24][25][26] which is implicated in neurogenerative diseases and type-2 diabetes. 28 This observation was very promising as it implies that there is a high probability of optimizing the selectivity of our leads for bacterial versus mammalian kinases. Compounds containing anilino-, indolo-, phenol-type substituents are potent inhibitors of GSK-3, while N-7 methylanilino and indolinyl-containing molecules are weak binders or gave inconclusive results for GSK-3 inhibition. ...
... Pan et al. designed and synthesized PROTAC 7 (9, Figure 4) based on their previous work. The compound significantly reduced BTK protein level and degraded the BLK protein (Chen J. et al., 2018;Xue et al., 2020). ...
