Highly Selective Inhibition of Tyrosine Kinase 2 (TYK2) for the Treatment of Autoimmune Diseases: Discovery of the Allosteric Inhibitor BMS-986165

Wrobleski, Stephen T.; Moslin, Ryan; Lin, Shuqun; Zhang, Yanlei; Spergel, Steven; Kempson, James; Tokarski, John S.; Strnad, Joann; Zupa-Fernandez, Adriana; Cheng, Lihong; Shuster, David J.; Gillooly, Kathleen M.; Yang, Xiaoxia; Heimrich, Elizabeth M.; McIntyre, Kim W.; Chaudhry, Charu; Khan, Javed; Ruzanov, Max; Tredup, Jeffrey; Mulligan, Dawn; Xie, Dan; Sun, Huadong; Huang, Christine; D’Arienzo, Celia; Aranı́bar, Nelly; Chiney, Manoj; Chimalakonda, Anjaneya; Pitts, William J.; Lombardo, Louis J.; Carter, Percy H.; Burke, James R.; Weinstein, David

doi:10.1021/acs.jmedchem.9b00444

Cited by 255 publications

(255 citation statements)

References 60 publications

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“…This goes in line with the requirement for enzymatically active TYK2 in the antiviral defense [19] but contrasts kinase-independent functions of TYK2 in NK cell-dependent tumour surveillance [8]. In support of our genetic data, we show that a TYK2-selective inhibitor [60] blocks LPS-induced upregulation of CASP11 in BMDMs and CASP5 in human macrophages. The second human CASP11 homolog CASP4 is constitutively expressed in most cell types [34] and not further upregulated by LPS [62].…”

Section: Discussionsupporting

confidence: 87%

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TYK2 licenses non-canonical inflammasome activation during endotoxemia

et al. 2020

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The non-canonical inflammasome is an emerging crucial player in the development of inflammatory and neurodegenerative diseases. It is activated by direct sensing of cytosolic lipopolysaccharide (LPS) by caspase-11 (CASP11), which then induces pyroptosis, an inflammatory form of regulated cell death. Here, we report that tyrosine kinase 2 (TYK2), a cytokine receptorassociated kinase, is a critical upstream regulator of CASP11. Absence of TYK2 or its kinase activity impairs the transcriptional induction of CASP11 in vitro and in vivo and protects mice from LPS-induced lethality. Lack of TYK2 or its enzymatic activity inhibits macrophage pyroptosis and impairs release of mature IL-1β and IL-18 specifically in response to intracellular LPS. Deletion of TYK2 in myeloid cells reduces LPS-induced IL-1β and IL-18 production in vivo, highlighting the importance of these cells in the inflammatory response to LPS. In support of our data generated with genetically engineered mice, pharmacological inhibition of TYK2 reduced LPS-induced upregulation of CASP11 in bone marrowderived macrophages (BMDMs) and of its homolog CASP5 in human macrophages. Our study provides insights into the regulation of CASP11 in vivo and uncovered a novel link between TYK2 activity and CASP11-dependent inflammation.

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Section: Discussionsupporting

confidence: 87%

“…To complement our genetic data, we tested whether pharmacological inhibition of TYK2 in BMDMs impairs LPSinduced upregulation of CASP11. Treatment with the allosteric TYK2 inhibitor BMS-986165 [60] inhibited the upregulation of CASP11 in a dose-dependent manner (Fig. 7a).…”

Section: Pharmacological Inhibition Of Tyk2 In Mouse and Human Macropmentioning

confidence: 92%

TYK2 licenses non-canonical inflammasome activation during endotoxemia

et al. 2020

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“…BMS-986165 selectively inhibits TYK2 74,75 . It binds exclusively to the active catalytic site of TYK2 which irreversibly inhibits TYK2 activation .…”

Section: New Jak Related Molecules In Deveopment In CDmentioning

confidence: 99%

“…BMS-986165 selectively inhibits TYK2. 74 , 75 It binds exclusively to the active catalytic site of TYK2, which irreversibly inhibits TYK2 activation. 74 A phase II placebo-controlled, randomized, multicentre, multidosing interventional study [LATTICE] has been initiated to evaluate the safety and efficacy of BMS-986165 for the induction and maintenance of remission in patients with moderate to severe CD.…”

Section: New Jak-related Molecules In Deveopment In CDmentioning

confidence: 99%

Efficacy of JAK inhibitors in Crohn’s Disease

Rogler

2019

Journal of Crohn's and Colitis

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Inhibition of Janus kinases in Crohn’s disease (CD) patients has shown conflicting results in clinical trials. Tofacitinib, a pan-JAK inhibitor showed efficacy in ulcerative colitis (UC) and has been approved for the treatment of patients with moderate to severe UC. In contrast, studies in patients suffering from CD were disappointing and the primary endpoint of clinical remission could not be met in the respective phase II induction and maintenance trials. Subsequently, the clinical development of tofacitinib was discontinued in CD. In contrast, efficacy of filgotinib, a selective JAK1 inhibitor, in CD patients was demonstrated in the randomized, double-blinded, placebo-controlled phase II FITZROY study. Upadacitinib also showed promising results in a phase II trial in moderate to severe CD. Subsequently phase III programs in CD have been initiated for both substances, which are still ongoing. Several newer molecules of this class of orally administrated immunosuppressants are tested in clinical programs. The concern of side effects of systemic JAK inhibition is addressed by either exclusively intestinal action or higher selectivity (Tyk2 inhibitors). In general, JAK inhibitors constitute a new promising class of drugs for the treatment of CD.

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“…Highlighted by Rino Ragno BMS-986165 is a new allosteric and selective inhibitor of tyrosine kinase 2 (TYK2) recently described by Wrobleski et al [29]. Different from other Janus family of kinase (JAK) inhibitors, BMS-986165 was demonstrated to be able to allosterically and highly selectively bind the TYK2 pseudokinase or "Janus Homology 2" (JH2) domain.…”

Section: Towards the Synthesis Of Highly Effective Treatment Of Autoimentioning

confidence: 99%