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IC50 value determined for DYRK1A inhibitors mentioned thorough this review. Abbrev. In order: ↑↑/↑↑↑ = moderate/most potent.
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Diabetes, and several diseases related to diabetes, including cancer, cardiovascular diseases and neurological disorders, represent one of the major ongoing threats to human life, becoming a true pandemic of the 21st century. Current treatment strategies for diabetes mainly involve promoting β-cell differentiation, and one of the most widely studie...
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... allows for high potency and selectivity for research compounds. In order to briefly summarize all the DYRK1A inhibitors discussed in this review, their IC50 values, targets, biological activity with future direction of development are listed in Table 2. ↑↑ key issues are the development of strategies to target regenerative compounds selectively to the β cell ↑↑ further optimization and elucidation of its molecular mechanism of action needed Compared to the well-known and the best to date inhibitor for increasing human pancreatic β-cell replication, the advantages of the newly identified fragments give us a privileged position in the race to the new therapeutics. ...Context 2
... allows for high potency and selectivity for research compounds. In order to briefly summarize all the DYRK1A inhibitors discussed in this review, their IC50 values, targets, biological activity with future direction of development are listed in Table 2. ↑↑ key issues are the development of strategies to target regenerative compounds selectively to the β cell ↑↑ further optimization and elucidation of its molecular mechanism of action needed Compared to the well-known and the best to date inhibitor for increasing human pancreatic β-cell replication, the advantages of the newly identified fragments give us a privileged position in the race to the new therapeutics. ...Citations
... The dual-specificity tyrosine phosphorylation-regulated kinase A (DYRK1A) is a kinase that phosphorylates proteins on serine/threonine. Activation of DYRK is obtained by phosphorylation of a tyrosine residue in the activation loop of the kinase (for review see [128]). Following activation, DYRK1A was reported to regulate various signaling pathways by activating or inactivating transcription and translation factors (RNA polymerase II CTD [129], Sprouty2 [130], DREAM complex [131], cAMP response element-binding protein (CREB) [132], and other proteins such as caspase-9 [133,134], Notch [135], and glycogen synthase [136]. ...
... Up-regulation of DYRK1A in beta-cells promoted a beta-cell mass expansion through increased cell proliferation and size [137]. Studies revealed a role for DYRK1A kinase in human β-cell replication, proliferation, and function [138,139], and suggested the development of potential therapeutic strategies targeting DYRK1A using DYRK1A inhibitors [128,[140][141][142][143]. Harmine and its derivatives are one of the most studied DYRK1A inhibitors [128,[140][141][142][143]. ...
... Up-regulation of DYRK1A in beta-cells promoted a beta-cell mass expansion through increased cell proliferation and size [137]. Studies revealed a role for DYRK1A kinase in human β-cell replication, proliferation, and function [138,139], and suggested the development of potential therapeutic strategies targeting DYRK1A using DYRK1A inhibitors [128,[140][141][142][143]. Harmine and its derivatives are one of the most studied DYRK1A inhibitors [128,[140][141][142][143]. ...
The prevalence of diabetes is increasing worldwide. Massive death of pancreatic beta-cells causes type 1 diabetes. Progressive loss of beta-cell function and mass characterizes type 2 diabetes. To date, none of the available antidiabetic drugs promotes the maintenance of a functional mass of endogenous beta-cells, revealing an unmet medical need. Dysfunction and apoptotic death of beta-cells occur, in particular, through the activation of intracellular protein kinases. In recent years, protein kinases have become highly studied targets of the pharmaceutical industry for drug development. A number of drugs that inhibit protein kinases have been approved for the treatment of cancers. The question of whether safe drugs that inhibit protein kinase activity can be developed and used to protect the function and survival of beta-cells in diabetes is still unresolved. This review presents arguments suggesting that several protein kinases in beta-cells may represent targets of interest for the development of drugs to treat diabetes.
... There is additional evidence that PTK signalling also has an important pathophysiological role in non-malignant diseases such as cardiac hypertrophy, pulmonary hypertension, lung fibrosis, rheumatoid disorders, atherosclerosis, and glomerulonephritis 8 . Several reports from clinical observations, animal models, and in vitro studies have documented the effect of TKIs in diabetes and its complications 9,10 . Tsatsoulis et al. 11 reviewed that targeting several PTKs may provide novel approaches for correcting the pathophysiologic disturbances of diabetes. ...
Protein tyrosine kinases (RTKs) modulate a wide range of pathophysiological events in several non-malignant disorders, including diabetic complications. To find new targets driving the development of diabetic cardiomyopathy (DCM), we profiled an RTKs phosphorylation array in diabetic mouse hearts and identified increased phosphorylated fibroblast growth factor receptor 1 (p-FGFR1) levels in cardiomyocytes, indicating that FGFR1 may contribute to the pathogenesis of DCM. Using primary cardiomyocytes and H9C2 cell lines, we discovered that high-concentration glucose (HG) transactivates FGFR1 kinase domain through toll-like receptor 4 (TLR4) and c-Src, independent of FGF ligands. Knocking down the levels of either TLR4 or c-Src prevents HG-activated FGFR1 in cardiomyocytes. RNA-sequencing analysis indicates that the elevated FGFR1 activity induces pro-inflammatory responses via MAPKs–NFκB signaling pathway in HG-challenged cardiomyocytes, which further results in fibrosis and hypertrophy. We then generated cardiomyocyte-specific FGFR1 knockout mice and showed that a lack of FGFR1 in cardiomyocytes prevents diabetes-induced cardiac inflammation and preserves cardiac function in mice. Pharmacological inhibition of FGFR1 by a selective inhibitor, AZD4547, also prevents cardiac inflammation, fibrosis, and dysfunction in both type 1 and type 2 diabetic mice. These studies have identified FGFR1 as a new player in driving DCM and support further testing of FGFR1 inhibitors for possible cardioprotective benefits.
... Unfortunately, most of the encouraging results come from preclinical studies performed in vitro and in vivo on various animal models. Keep in mind, however, that even the best animal model will not reflect each individual tumor-bearing patient often suffering from other disorders [445,446]. In most clinical cases, PDT alone is not sufficient to induce a proper immune response, as cancer cells also release immunosuppressive cytokines or other promoting molecules through non-immunogenic pathways. ...
Innovative anticancer therapies based on the activation of the immune system offer promise in the battle against cancers resistant to traditional treatments. Examples of such therapeutic approaches include, along with various types of immunotherapies, photodynamic therapy (PDT). PDT is a photochemistry-based strategy that results not only from its direct effects on cancer cells but also from disruption of tumor vasculature and activation of the host immune system. However, to achieve therapeutic success manifested in the eradication of the primary tumor and distant metastases, it is necessary to design suitable photosensitizers (PSs) with the desired optical and photo-physical properties to enable efficient generation of ROS under tumor microenvironmental (TME) conditions, especially hypoxia. Thus, in this review particular attention is paid to the photochemical properties of PSs, notably the sufficiently long-lived triplet states and mechanisms of energy/electron transfer reactions. Photo-generated ROS initiate inflammatory reaction, expression of heat-shock proteins, infiltration of immune cells and long-term immune memory. These unique features of PDT give new possibilities to combine PDT with agents stimulating immune response as well as with immunotherapy, especially based on PD-1/PD-L1 blockade. Most of the systems explored in this aspect so far are either derivatives of naturally occurring metal complexes (Heme, Chlorophyll a, and Bacteiochorophyll a-inspired PSs), synthetic (metallo)porphyrins, and (metallo)phthalocya-nines or hybrid materials containing metal nanoparticles. This work also summarizes recent reports on the synthesis of antibody-PS conjugates with desired spectroscopic and photochemical properties along with enhanced selectivity and biological activity. Finally, the most notable drawbacks of PDT are presented, and a scenario is outlined for the development of PDT alone, and combined with immunotherapy to overcome these challenges in the future.
... The diabetic kinome is composed of protein kinases known to play a key role in modulating cell processes engaged in diabetes progression 21,22 . Small molecules that target kinase proteins have been shown to be successful in animal models of insulin resistance and diabetes, primarily by re-establishing insulin homeostasis 23,24 . ...
The selective inhibition of kinases from the diabetic kinome is known to promote the regeneration of beta cells and provide an opportunity for the curative treatment of diabetes. The effect can be achieved by carefully tailoring the selectivity of inhibitor toward a particular kinase, especially DYRK1A, previously associated with Down syndrome and Alzheimer's disease. Recently DYRK1A inhibition has been shown to promote both insulin secretion and beta cells proliferation. Here, we show that commonly available flavones are effective inhibitors of DYRK1A. The observed biochemical activity of flavone compounds is confirmed by crystal structures solved at 2.06 Å and 2.32 Å resolution, deciphering the way inhibitors bind in the ATP-binding pocket of the kinase, which is driven by the arrangement of hydroxyl moieties. We also demonstrate antidiabetic properties of these biomolecules and prove that they could be further improved by therapy combined with TGF-β inhibitors. Our data will allow future structure-based optimization of the presented scaffolds toward potent, bioavailable and selective anti-diabetic drugs.
... Numerous pharmacological inhibitors against DYRK1A have been reported [15,17,[41][42][43][44][45][46]. Among these, we selected leucettines, which represent a group of well-characterized DYRK1A inhibitors derived from the leucettamine B (marine sponge alkaloid) (Fig 1) [24, 27-29, [47][48][49][50][51][52]. ...
The decreased β-cell mass and impaired β-cell functionality are the primary causes of diabetes mellitus (DM). Nevertheless, the underlying molecular mechanisms by which β-cell growth and function are controlled are not fully understood. In this work, we show that leucettines, known to be DYRK1A kinase inhibitors, can improve glucose-stimulated insulin secretion (GSIS) in rodent β-cells and isolated islets, as well as in hiPSC-derived β-cells islets. We confirm that DYRK1A is expressed in murine insulinoma cells MIN6. In addition, we found that treatment with selected leucettines stimulates proliferation of β-cells and promotes MIN6 cell cycle progression to the G2/M phase. This effect is also confirmed by increased levels of cyclin D1, which is highly responsive to proliferative signals. Among other leucettines, leucettine L43 had a negligible impact on β-cell proliferation, but markedly impair GSIS. However, leucettine L41, in combination with LY364947, a, a potent and selective TGF-β type-I receptor, significantly promotes GSIS in various cellular diabetic models, including MIN6 and INS1E cells in 2D and 3D culture, iPSC-derived β-cell islets derived from iPSC, and isolated mouse islets, by increased insulin secretion and decreased glucagon level. Our findings confirm an important role of DYRK1A inhibitors as modulators of β-cells function and suggested a new potential target for antidiabetic therapy. Moreover, we show in detail that leucettine derivatives represent promising antidiabetic agents and are worth further evaluation, especially in vivo.
... 14 More recent findings also implicated the role of DYRK1A in cancer. 15,16 DYRK1A phosphorylation primes the substrates for subsequent phosphorylation by a processive kinase, the constitutively active glycogen synthase kinase-3β (GSK3β). 17,18 GSK3β phosphorylates more than a hundred different substrates 19 and has been implicated in diverse cellular processes, including embryogenesis, immune response, inflammation, apoptosis, autophagy, wound healing, neurodegeneration, and carcinogenesis. ...
A clinical casein kinase 2 inhibitor, CX-4945 (silmitasertib), shows significant affinity toward the DYRK1A and GSK3β kinases, involved in down syndrome phenotypes, Alzheimer's disease, circadian clock regulation, and diabetes. This off-target activity offers an opportunity for studying the effect of the DYRK1A/GSK3β kinase system in disease biology and possible line extension. Motivated by the dual inhibition of these kinases, we solved and analyzed the crystal structures of DYRK1A and GSK3β with CX-4945. We built a quantum-chemistry-based model to rationalize the compound affinity for CK2α, DYRK1A, and GSK3β kinases. Our calculations identified a key element for CK2α's subnanomolar affinity to CX-4945. The methodology is expandable to other kinase selectivity modeling. We show that the inhibitor limits DYRK1A- and GSK3β-mediated cyclin D1 phosphorylation and reduces kinase-mediated NFAT signaling in the cell. Given the CX-4945's clinical and pharmacological profile, this inhibitory activity makes it an interesting candidate with potential for application in additional disease areas.
... However, numerous biological targets have been studied in this context, including DYRK1A. Studies show that DYRK1A small molecule inhibitors induce human βcell proliferation both in vitro and in vivo [54,78,[114][115][116][117][118]. Several studies have demonstrated that DYRK1A overexpression attenuated β-cell proliferation through NFAT dysregulation, a transcription factor that transactivates cell cycle-activating genes and represses cell cycle inhibitor genes including other CMGC, cyclins and p57 (Table 1) [30,68,114,115]. ...
The increasing population will challenge healthcare, particularly because the worldwide population has never been older. Therapeutic solutions to age-related disease will be increasingly critical. Kinases are key regulators of human health and represent promising therapeutic targets for novel drug candidates. The dual-specificity tyrosine-regulated kinase (DYRKs) family is of particular interest and, among them, DYRK1A has been implicated ubiquitously in varied human diseases. Herein, we focus on the characteristics of DYRK1A, its regulation and functional role in different human diseases, which leads us to an overview of future research on this protein of promising therapeutic potential.
Diabetes Mellitus (DM) is a chronic metabolic disorder characterized by β-cell loss and inflammation. From a therapeutic standpoint, it would be necessary to halt the uncontrolled inflammatory response and to enable the regeneration of the damaged β-cells. In this work, to achieve the latter two drug-loaded nanocarrier systems have been developed and evaluated in-vivo in DM mouse model. For β-cell proliferation, small chitosan (CS) nanoparticles (NPs) (201 ± 30 nm) were loaded with 4b, a selective inhibitor of DYRK1A (dual-specificity tyrosine phosphorylation-regulated kinase 1A). To reduce inflammation, large poly lactic-co-glycolic acid (PLGA) microparticles (MPs) (1172 ± 77 nm) were encapsulated with BI-605906, an inhibitor of IKKβ (inhibitor of kappa B kinase beta), acting as an inhibitor of an inhibitor. The EE% values were 90 ± 4.2 % and 87 ± 4.46 % for 4b–CS–NPs and BI-605906-PLGA-MPs, respectively. In-vivo biodistribution studies indicated the ability of both particles to accumulate in the pancreas. For CS-NPs, this was achieved as a function of the increased vascular permeability in DM, whereas for PLGA-MPs, this was achieved as function of macrophage uptake. Treatment with 4b–CS–NPs (but not the unloaded drug) reduced blood glucose levels (BGLs) and elevated cyclin D1 (CD1) gene expression indicating the successful ability of the NP system in promoting β-cells proliferation. Although treatment with free BI-605906 showed a modest reduction in BGLs, BI-605906-PLGA-MPs showed no improvement in BGLs. The latter could possibly be attributed to sub-optimal dosing. These results indicate that 4b–CS–NPs have the potential to lower BGLs by promoting β-cell proliferation and restoring pancreatic function. Further optimization is needed for BI-605906-PLGA-MPs, which may enhance therapeutic outcome by dual therapy.
Chromothripsis, the process of catastrophic shattering and haphazard repair of chromosomes, is a common event in cancer. Whether chromothripsis might constitute an actionable molecular event amenable to therapeutic targeting remains an open question. We describe recurrent chromothripsis of chromosome 21 in a subset of patients in blast phase of a myeloproliferative neoplasm (BP-MPN), which alongside other structural variants leads to amplification of a region of chromosome 21 in ~25% of patients (chr21amp). We report that chr21amp BP-MPN has a particularly aggressive and treatment- resistant phenotype. The chr21amp event is highly clonal and present throughout the hematopoietic hierarchy. DYRK1A, a serine threonine kinase and transcription factor, is the only gene in the 2.7Mb minimally amplified region which showed both increased expression and chromatin accessibility compared to non-chr21amp BP-MPN controls. We demonstrate that DYRK1A is a central node at the nexus of multiple cellular functions critical for BP-MPN development, including DNA repair, STAT signalling and BCL2 overexpression. DYRK1A is essential for BP-MPN cell proliferation in vitro and in vivo, and DYRK1A inhibition synergises with BCL2 targeting to induce BP- MPN cell apoptosis. Collectively, these findings define the chr21amp event as a prognostic biomarker in BP-MPN and link chromothripsis to a druggable target.
