Snahel Patel

Abstract 5762: FMC-242, a highly potent and selective covalent inhibitor of the PI3Kα -RAS interaction, demonstrates robust anti-tumor activity as monotherapy and in combination with targeted therapies

Kevin R. Webster, Ryan McFadden, Abdul Awol, Koli Basu et autres

Abstract Activation of RAS and PI3Kα are the most frequent oncogenic events in cancer, playing a key role in many aspects of tumor cell physiology, including growth, survival, differentiation, and migration. While treatment options have recently emerged for a subset of KRAS …

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Discovery of Clinical Candidate GDC-8264, a Novel, Potent and Selective RIP1 Inhibitor for Amelioration of Tissue Damage and the Treatment of Inflammatory Diseases

Snahel Patel, Huifen Chen, Eugene Varfolomeev, Youngsu Kwon et autres

Abstract Receptor-interacting protein 1 (RIP1) is a critical regulator of inflammatory cell death induced by diverse stimuli including TNF family ligands and ischemic injury. As such, the inhibition of RIP1 with small molecule kinase inhibitors is predicted to ameliorate tissue damage and …

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Abstract 3787: Restoring the function of the guardian of the genome: FMC-220 a highly potent and selective covalent activator of p53 Y220C

John-Paul Upton, Irina Dotsenko, Vikram M. Narayan, Marya Liimatta et autres

Loss of function mutations of the TP53 gene are the most common genetic defects across all human cancers. These mutations have long been intractable to drug development. The p53 Y220C mutation is common, occurring in ∼1% of cancers, leading to destabilization, aggregation …

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Abstract 1142: Discovery of FMC-376 a novel orally bioavailable inhibitor of activated KRASG12C

Snahel Patel, Barun Bhhatarai, Philamer Calses, Daniel Erlanson et autres

Abstract KRAS is one of the most frequently mutated genes in cancer and was long considered undruggable until the recent discovery of inhibitors that bind the inactive (GDP-bound) form of KRASG12C. The most clinically advanced of these first-generation molecules have demonstrated clinical …

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Phenotypic screening with deep learning identifies HDAC6 inhibitors as cardioprotective in a BAG3 mouse model of dilated cardiomyopathy

Jin Yang, Francis Grafton, Sara Ranjbarvaziri, Ana Budan et autres

Dilated cardiomyopathy (DCM) is characterized by reduced cardiac output, as well as thinning and enlargement of left ventricular chambers. These characteristics eventually lead to heart failure. Current standards of care do not target the underlying molecular mechanisms associated with genetic forms of …

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Abstract 3601: Discovery of novel dual-acting KRASG12C inhibitors that target both the active and inactive forms of the protein

Philamer Calses, Jacob Corpuz, Susan Fong, Phil Gerkin et autres

Abstract KRAS is one of the most frequently mutated genes in cancer with alterations occurring in > 14% of all tumors. Recent advances have led to the discovery and development of inhibitors that bind the inactive (GDP-bound) form of KRASG12C. The most …

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Structure-Based Design of Potent, Selective, and Orally Bioavailable VPS34 Kinase Inhibitors

Dennis X. Hu, Snahel Patel, Huifen Chen, Shu‐Mei Wang et autres

VPS34 is a class III phosphoinositide 3-kinase involved in endosomal trafficking and autophagosome formation. Inhibitors of VPS34 were believed to have value as anticancer agents, but genetic and pharmacological data suggest that sustained inhibition of VPS34 kinase activity may not be well …

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Deep learning detects cardiotoxicity in a high-content screen with induced pluripotent stem cell-derived cardiomyocytes

Francis Grafton, Jaclyn J. Ho, Sara Ranjbarvaziri, Farshad Farshidfar et autres

Drug-induced cardiotoxicity and hepatotoxicity are major causes of drug attrition. To decrease late-stage drug attrition, pharmaceutical and biotechnology industries need to establish biologically relevant models that use phenotypic screening to detect drug-induced toxicity in vitro. In this study, we sought to rapidly …

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Author response: Deep learning detects cardiotoxicity in a high-content screen with induced pluripotent stem cell-derived cardiomyocytes

Francis Grafton, Jaclyn J. Ho, Sara Ranjbarvaziri, Farshad Farshidfar et autres

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Deep Learning Predicts Patterns of Cardiotoxicity in a High-Content Screen Using Induced Pluripotent Stem Cell–Derived Cardiomyocytes

Francis Grafton, Jaclyn J. Ho, Sara Ranjbarvaziri, Farshad Farshidfar et autres

ABSTRACT Drug-induced cardiotoxicity and hepatotoxicity are major causes of drug attrition. To decrease late-stage drug attrition, pharmaceutical and biotechnology industries need to establish biologically relevant models that use phenotypic screening to predict drug-induced toxicity. In this study, we sought to rapidly detect …

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RIP1 kinase activity is critical for skin inflammation but not for viral propagation

Joshua D. Webster, Youngsu Kwon, Summer Park, Hua Zhang et autres

Receptor interacting protein kinase 1 (RIP1) is a critical effector of inflammatory responses and cell death activation. Cell death pathways regulated by RIP1 include caspase-dependent apoptosis and caspase-independent necroptosis. The kinase activity of RIP1 has been associated with a number of inflammatory, …

RIP1 inhibition blocks inflammatory diseases but not tumor growth or metastases

Snahel Patel, Joshua D. Webster, Eugene Varfolomeev, Youngsu Kwon et autres

The kinase RIP1 acts in multiple signaling pathways to regulate inflammatory responses and it can trigger both apoptosis and necroptosis. Its kinase activity has been implicated in a range of inflammatory, neurodegenerative, and oncogenic diseases. Here, we explore the effect of inhibiting …

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