Journal ArticleDOI
Discovery of a First-in-Class Receptor Interacting Protein 1 (RIP1) Kinase Specific Clinical Candidate (GSK2982772) for the Treatment of Inflammatory Diseases
Philip A. Harris,Scott B. Berger,Jae U. Jeong,Rakesh Nagilla,Deepak Bandyopadhyay,Nino Campobasso,Carol A. Capriotti,Julie A. Cox,Lauren Dare,Xiaoyang Dong,Patrick M. Eidam,Joshua N. Finger,Sandra J. Hoffman,James Kang,Viera Kasparcova,Bryan W. King,Ruth Lehr,Yunfeng Lan,Lara Kathryn Leister,John D. Lich,Thomas T. MacDonald,Nathan A. Miller,Michael T. Ouellette,Christina S. Pao,Attiq Rahman,Michael Reilly,Alan R. Rendina,Elizabeth J. Rivera,Michelle C. Schaeffer,Clark A. Sehon,Robert Singhaus,Helen H. Sun,Barbara A. Swift,Rachel D. Totoritis,Anna Vossenkämper,Paris Ward,David D. Wisnoski,Daohua Zhang,Robert W. Marquis,Peter J. Gough,John Bertin +40 more
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TLDR
Lead optimization of a benzoxazepinone hit from a DNA-encoded library and the discovery and profile of clinical candidate GSK2982772 (compound 5), currently in phase 2a clinical studies for psoriasis, rheumatoid arthritis, and ulcerative colitis, highlight its potential as a novel anti-inflammatory agent.Abstract:
RIP1 regulates necroptosis and inflammation and may play an important role in contributing to a variety of human pathologies, including immune-mediated inflammatory diseases. Small-molecule inhibitors of RIP1 kinase that are suitable for advancement into the clinic have yet to be described. Herein, we report our lead optimization of a benzoxazepinone hit from a DNA-encoded library and the discovery and profile of clinical candidate GSK2982772 (compound 5), currently in phase 2a clinical studies for psoriasis, rheumatoid arthritis, and ulcerative colitis. Compound 5 potently binds to RIP1 with exquisite kinase specificity and has excellent activity in blocking many TNF-dependent cellular responses. Highlighting its potential as a novel anti-inflammatory agent, the inhibitor was also able to reduce spontaneous production of cytokines from human ulcerative colitis explants. The highly favorable physicochemical and ADMET properties of 5, combined with high potency, led to a predicted low oral dose in humans.read more
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Journal ArticleDOI
Kinase inhibitors: the road ahead
TL;DR: An overview of the novel targets, biological processes and disease areas that kinase-targeting small molecules are being developed against, highlight the associated challenges and assess the strategies and technologies that are enabling efficient generation of highly optimized kinase inhibitors are provided.
Journal ArticleDOI
Necroptosis and RIPK1-mediated neuroinflammation in CNS diseases.
TL;DR: The evidence implicating necroptosis in neurological diseases is outlined and it is suggested that targeting RIPK1 might help to inhibit multiple cell death pathways and ameliorate neuroinflammation.
Journal ArticleDOI
Expanding the medicinal chemistry synthetic toolbox
TL;DR: Opportunities for the expansion of the medicinal chemists' synthetic toolbox are highlighted to enable enhanced impact of new methodologies in future drug discovery.
Journal ArticleDOI
Necroptosis in development and diseases.
TL;DR: RIPK1 inhibition represents a key therapeutic strategy for treatment of diseases where blocking both necroptosis and apoptosis can be beneficial and regulating the activation of RIPK1 by ubiquitination and phosphorylation is critical.
Journal ArticleDOI
Trends in kinase drug discovery: targets, indications and inhibitor design.
Misty M. Attwood,Doriano Fabbro,Aleksandr V. Sokolov,Stefan Knapp,Stefan Knapp,Helgi B. Schiöth,Helgi B. Schiöth +6 more
TL;DR: In this paper, the authors analyzed the landscape of approved and investigational therapies that target kinases and trends within it, including the most popular targets of kinase inhibitors and their expanding range of indications.
References
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Journal ArticleDOI
Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury
Alexei Degterev,Zhihong Huang,Michael Boyce,Yaqiao Li,Prakash Jagtap,Noboru Mizushima,Gregory D. Cuny,Timothy J. Mitchison,Michael A. Moskowitz,Junying Yuan +9 more
TL;DR: It is demonstrated that necroptosis contributes to delayed mouse ischemic brain injury in vivo through a mechanism distinct from that of apoptosis and offers a new therapeutic target for stroke with an extended window for neuroprotection.
Journal ArticleDOI
Identification of RIP1 kinase as a specific cellular target of necrostatins.
Alexei Degterev,Junichi Hitomi,Megan Germscheid,Irene L. Ch’en,Olga Korkina,Xin Teng,Derek W. Abbott,Derek W. Abbott,Gregory D. Cuny,Chengye Yuan,Gerhard Wagner,Stephen M. Hedrick,Scott A. Gerber,Alexey Lugovskoy,Alexey Lugovskoy,Junying Yuan +15 more
TL;DR: Necroptosis is a cellular mechanism of necrotic cell death induced by apoptotic stimuli in the form of death domain receptor engagement by their respective ligands under conditions where apoptotic execution is prevented and necrostatins are established as the first-in-class inhibitors of RIP1 kinase, the key upstream kinase involved in the activation of necroptosis.
Journal ArticleDOI
Caspase-8 regulates TNF-α-induced epithelial necroptosis and terminal ileitis
Claudia Günther,Eva Martini,Nadine Wittkopf,Kerstin Amann,Benno Weigmann,Helmut Neumann,Maximilian J. Waldner,Stephen M. Hedrick,Stefan Tenzer,Markus F. Neurath,Christoph Becker +10 more
TL;DR: A critical function of caspase-8 is demonstrated in regulating intestinal homeostasis and in protecting IECs from TNF-α-induced necroptotic cell death and high levels of RIP3 in human Paneth cells and increased ne croptosis in the terminal ileum of patients with Crohn’s disease are identified, suggesting a potential role of necropsies in the pathogenesis of this disease.
Journal ArticleDOI
Necroptosis as an alternative form of programmed cell death
TL;DR: Interestingly, a death-domain containing kinase, RIP1, is involved in mediating all three pathways, with its kinase activity specifically involved in regulating necroptosis.
Journal ArticleDOI
A Small Molecule Smac Mimic Potentiates TRAIL- and TNFα-Mediated Cell Death
Lin Li,Ranny Mathew Thomas,Hidetaka Suzuki,Jef K. De Brabander,Xiaodong Wang,Patrick G. Harran +5 more
TL;DR: The molecule has allowed a temporal, unbiased evaluation of the roles that IAP proteins play during signaling from TRAIL and TNF receptors and is a lead structure for the development of IAP antagonists potentially useful as therapy for cancer and inflammatory diseases.