Extended Kinase Selectivity and SafetyScreen44 Profiling Data for ALK2 Inhibitors

Résumé fourni par la source

Diffuse Intrinsic Pontine Glioma (DIPG) is a rare and aggressive pediatric cancer located in the pons region of the brainstem, classified as a broader class of H3 K27M mutant Diffuse Midline Gliomas (DMG). Traditional drug development models struggle to address rare diseases like DIPG due to small patient populations and high risks. M4K Pharma focuses on developing an ALK2 enzyme inhibitor, the first therapeutic designed specifically for DIPG. We are leveraging highly potent, selective, and drug-like molecules targeting this protein to create a promising therapeutic option for children affected by this devastating disease. The following datasets evaluate the off-target pharmacology and kinase selectivity profiles of multiple ALK2 inhibitor compounds using broad biochemical screening panels, kinase profiling assays, and radioligand binding studies. Compounds including M4K2009, M4K2281, and M4K2308 were tested across diverse receptors, ion channels, transporters, and kinases to identify secondary pharmacological activities and potential safety liabilities. Dose-response analyses and IC₅₀ determinations were performed against off-target kinases including ACTR2, BRK, DDR1, RIPK2, TNIK, ZAK, and Abl, while SafetyScreen44 profiling assessed interactions with neurological and cardiovascular-associated targets such as adrenergic receptors, cannabinoid CB1, sodium channels, and the hERG potassium channel. Complementing these studies, extended kinase profiling data for M4K2117, M4K2118, M4K2143, M4K2163, M4K2214, M4K2234, M4K2236, and M4K2238 demonstrate consistently high kinase selectivity across broad kinase panels and limited off-target kinase activity. Collectively, these findings indicate that the favorable selectivity profile is a general characteristic of the M4K ALK2 inhibitor series rather than an isolated property of individual analogues, providing an integrated assessment of compound selectivity and off-target risk to support optimization of ALK2-targeted therapies for DIPG. Table of key terms and definitions of the project. Keyword Definition DIPG Diffuse Intrinsic Pontine Glioma, an aggressive pediatric brainstem tumor with poor prognosis and limited treatment options. ALK2 / ACVR1 A serine/threonine kinase receptor involved in BMP signaling and frequently mutated in a subset of DIPG tumors. Off-Target Profiling Evaluation of compound activity against unintended biological targets to assess selectivity and safety risk. Kinase Selectivity The ability of a compound to preferentially inhibit a desired kinase target over other kinases. IC₅₀ The concentration of a compound required to inhibit 50% of target activity; commonly used to measure potency. SafetyScreen44 A broad pharmacology screening panel designed to identify potential off-target interactions associated with safety liabilities. CB1 Receptor Cannabinoid receptor type 1 involved in neurological signaling and commonly assessed in CNS safety profiling. RIPK2 / DDR1 / BRK / TNIK / ZAK Off-target kinases evaluated to determine inhibitor selectivity and broader kinase interaction profiles.

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