Pre-clinical evaluation of TYK2 inhibitors for beta cell protection in type 1 diabetes
Alexandra Coomans de BrachèneÂngela CastelaRaghavendra MirmiraPiero MarchettiWenyan MiaoCarmella Evans‐MolinaDécio L. Eizirik
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BETA (programming language)
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Protein tyrosine phosphatase 1 B (PTP1B) is involved in the development of obesity, type 2 diabetes, and different cancer cells, such as breast cancer and lung cancer. This makes the enzyme a promising target for the treatment of these diseases. The purpose of this review is to present the studies on the role of PTP1B in the development of obesity, diabetes, and cancer and selected inhibitors as a possible treatment. Studies have shown that PTP1B, due to its implication in obesity, type 2 diabetes, and oncogenic transformation, denotes a promising drug target. The selected compounds that are effective PTP1B inhibitors can be considered promising anti-obesity, anti-diabetic, and anticancer treatment.
Drug Development
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Type 1 diabetes (T1D) (previously insulin-dependent or juvenile-onset diabetes) is one of the two major forms of human diabetes [1].T1D is caused by an autoimmune process involving T cells, B cells, monocyte macrophages, and dendritic cells, with the major pathology being the development of destructive T-cell infiltration of insulin-producing β cells in the pancreas.Disease occurs from the unfavorable balance of susceptibility and resistance genes, and is thought to have an unidentified environmental trigger.The β-cell destruction results in an absolute deficiency of insulin with chronic hyperglycemia.Medical treatment is insulin administration for life and therapeutic attention to comorbidities, such as hyperlipidemia and hypertension.The pathological consequences of the diabetic milieu, predominantly hyperglycemia, are known as "complications", and these include vasculopathies of increased and premature strokes, heart attacks, limb amputations, kidney disease, and blindness.Evidence suggests that T1D might also be associated with peripheral insulin resistance[2,3], the precipitating factor in obesity-induced Type 2 diabetes (T2D), and there might be closer associations between these two most prominent forms of diabetes than previously recognized.T1D is a devastating disease because it can commence at a very young age and requires lifelong multiple daily insulin injections and constant invasive monitoring of blood glucose levels.T1D commences mostly with rapid onset in children and young adults.The prevalence of T1D is increasing, especially in older subjects, but the reasons for this are unknown.Most of the advances in the understanding of this disease over the last 3 decades have been from an immunological and genetic perspective.In the 1980s, physician scientists, immunologists, and diabetologists offered the hope that T1D would be cured by the end of the 20 th century.Despite extensive research and many immunologically based trials, this outcome did not eventuate and there remains no therapeutic intervention for the prevention or cure of this disease to this day.
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Introduction: Some inhibitors of tyrosine kinase, as imatinib, erlotinib and sunitinib have antihyperglycemic effects but the mechanisms are not totally clear. Areas covered: It is well established that insulin resistance and beta-cell failure are hallmarks of type 2 diabetes mellitus (DM2). The present review will discuss the molecular mechanisms that account for insulin resistance and beta-cell failure in DM2, and also the effect of tyrosine kinase inhibitors in these processes. Expert opinion: A better understanding of how these drugs improve the two most important mechanisms of DM2 associated with suggestions of clinical studies will lead to improve the treatment of this disease.
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Abstract The loss of functional insulin-producing β-cells is a hallmark of diabetes. Mammalian sterile 20-like kinase 1 (MST1) is a key regulator of pancreatic β-cell death and dysfunction; its deficiency restores functional β-cells and normoglycemia. The identification of MST1 inhibitors represents a promising approach for a β-cell-protective diabetes therapy. Here, we identify neratinib, an FDA-approved drug targeting HER2/EGFR dual kinases, as a potent MST1 inhibitor, which improves β-cell survival under multiple diabetogenic conditions in human islets and INS-1E cells. In a pre-clinical study, neratinib attenuates hyperglycemia and improves β-cell function, survival and β-cell mass in type 1 (streptozotocin) and type 2 (obese Lepr db/db ) diabetic mouse models. In summary, neratinib is a previously unrecognized inhibitor of MST1 and represents a potential β-cell-protective drug with proof-of-concept in vitro in human islets and in vivo in rodent models of both type 1 and type 2 diabetes.
Neratinib
Pancreatic Islets
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Background: Janus kinases (JAKs) are important regulators of intracellular responses triggered by many key proinflammatory cytokines and are clinically validated therapeutic targets for treating various autoimmune diseases. However, current approved JAK inhibitors failed to achieve maximal clinical benefit in part due to their unfavorable selectivity for individual JAKs such as JAK2 and/or JAK3, leading to dose-limiting toxicities or severe toxicities (e.g., thrombosis, anemia, immune suppression). Selective inhibition of JAK1 and/or TYK2 may minimize or avoid some of the toxicities and potentially offer a better therapeutic window for treating autoimmune diseases. No highly selective JAK1/TYK2 inhibitor has been reported to date. Objectives: Discovery of a highly selective JAK1/TYK2 inhibitor that maximally avoids JAK2 and JAK3 inhibition. We described preclinical characterization of a novel, highly potent and selective JAK1/TYK2 inhibitor TLL018 and its potential utility in treating autoimmune diseases such as rheumatoid arthritis (RA). Methods: Using predicting SAR, TLL018 was designed to achieve exquisite selectivity for both JAK1 and TYK2 while sparing JAK2, JAK3 and other human kinases. Its enzyme and cell activities, kinase selectivity, and in vivo efficacy were assessed in a battery of relevant enzyme, cell and whole blood assays, and in vivo arthritis animal models. Additional preclinical DMPK and toxicology studies were conducted to support its clinical development. Results: TLL018 is a highly potent and selective, orally bioavailable JAK1/TYK2 inhibitor against JAK1 (IC 50 = 4 nM) and TYK2 (IC 50 = 5 nM) as measured in in vitro kinase assays with ATP concentrations at individual Km. Its potency against JAK2 or JAK3 is greater than 1 µM. Profiling against a panel of over 350 human kinase showed that TLL018 is exclusively selective for JAK1 and TYK2, with ≥ 90-fold selectivity against all other kinases tested. TLL018 exhibited potent cellular activity for JAK1-mediated IL-6 signaling (IC 50 = 0.6 µM) with greater than 100-fold selectivity against JAK2-mediated cytokine (e.g., TPO) signaling in human whole blood-based assays. Oral administration of TLL018 demonstrated dose-dependent efficacy in commonly studied rat adjuvant-induced arthritis (rAIA) model and mouse collagen-induced arthritis (mCIA) model. Significant inhibition of inflammation, bone resorption, splenomegaly and body weight change was observed in adjuvant-induced disease in rats. In addition, significant inhibition of inflammation, cartilage destruction, bone resorption and histological signs was demonstrated in collagen-induced arthritis in mice. Noticeably, TLL018 exhibited significant anti-inflammation activity at doses that only blocked JAK1 and TYK2 and exerted little inhibition of JAK2 and JAK3. In support of clinical development of TLL018, preclinical ADME and PK studies and IND-enabling toxicology and safety pharmacology studies were completed, confirming that TLL018 possesses excellent ADME and PK properties, and exhibits a clean on-target safety profile. Conclusion: TLL018 is a highly potent and selective JAK1/TYK2 inhibitor that demonstrated excellent efficacy and tolerability in relevant mouse and rat arthritis models. The collective data of its preclinical pharmacology, PK and toxicology showed a favorable pharmaceutical profile, further supporting its development for treating autoimmune diseases including RA. Clinical evaluation of TLL018 is ongoing. Disclosure of Interests: Xiangdong Liu Shareholder of: I own shares of TLL Pharmaceutical LLC, Employee of: I am employed by TLL Pharmaceutical LLC, Fenlai Tan Shareholder of: I own shares of TLL Pharmaceutical LLC, Employee of: I am employed by TLL Pharmaceutical LLC, Chris Liang Shareholder of: I own shares of TLL Pharmaceutical LLC, Employee of: I am employed by TLL Pharmaceutical LLC
Tyrosine kinase 2
Proinflammatory cytokine
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Allosteric modulator
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Researchers recently performed a control trial to test the efficacy of BMS-986165 a potent TYK2 inhibitor. Here's what they found.
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The recent development of small-molecule tyrosine kinase (TK) inhibitors offers increasing opportunities for the treatment of autoimmune diseases. In this study, we investigated the potential of this new class of drugs to treat and cure type 1 diabetes (T1D) in the NOD mouse. Treatment of prediabetic and new onset diabetic mice with imatinib (Gleevec) prevented and reversed T1D. Similar results were observed with sunitinib (Sutent), an additional approved multikinase inhibitor, suggesting that the primary target of imatinib, c-Abl, was not essential in blocking disease in this model. Additional studies with another TK inhibitor, PLX647 (targeting c-Kit and c-Fms) or an anti-c-Kit mAb showed only marginal efficacy whereas a soluble form of platelet-derived growth factor receptor (PDGFR), PDGFRbetaIg, rapidly reversed diabetes. These findings strongly suggest that inhibition of PDGFR is critical to reverse diabetes and highlight a crucial role of inflammation in the development of T1D. These conclusions were supported by the finding that the adaptive immune system was not significantly affected by imatinib treatment. Finally, and most significantly, imatinib treatment led to durable remission after discontinuation of therapy at 10 weeks in a majority of mice. Thus, long-term efficacy and tolerance is likely to depend on inhibiting a combination of tyrosine kinases supporting the use of selective kinase inhibitors as a new, potentially very attractive approach for the treatment of T1D.
Imatinib Mesylate
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Altered tyrosine kinase signalling has been implicated in several diseases, paving the way for the development of small-molecule TKIs (tyrosine kinase inhibitors). TKIs such as imatinib, sunitinib and dasatinib are clinically used for treating chronic myeloid leukaemia, gastrointestinal stromal tumours and other malignancies. In addition to their use as anti-cancer agents, increasing evidence points towards an anti-diabetic effect of these TKIs. Imatinib and other TKIs counteract diabetes not only in non-obese diabetic mice, but also in streptozotocin diabetic mice, db/db mice, high-fat-treated rats and humans with T2D (Type 2 diabetes). Although the mechanisms of protection need to be investigated further, the effects of imatinib and other TKIs in human T2D and the rapidly growing findings from animal models of T1D (Type 1 diabetes) and T2D are encouraging and give hope to improved treatment of human diabetes. In the present article, we review the anti-diabetic effects of TKIs which appear to involve both protection against β-cell death and improved insulin sensitivity. Considering the relatively mild side effects of TKIs, we hypothesize that TKIs could be used to treat new-onset T1D, prevent T1D in individuals at high risk of developing the disease, treat the late stages of T2D and improve the outcome of islet transplantation.
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