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Why is the pan-KRAS inhibitor, BI-2493, a big deal? The RAS proteins, KRAS4A, KRAS4B, HRAS, and NRAS control diverse cellular processes, and gain-of-function mutations in RAS genes are found in ~25% of cancers in humans, with KRAS mutations accounting for up to 85% of RAS mutations across cancers. While KRAS(G12C) has been successfully targeted by…

A protein degradation approach to overcome paradoxical RAF activation. CFT1946 from C4 Therapeutics is a potent, selective, and orally bioavailable bifunctional degrader of mutant BRAF in Ph. I/II for the treatment of BRAF-driven solid tumors, alone and in combo with a MEK1/2 inhibitor (trametinib) (NCT05668585). BRAF-V600X is clinically validated with approved drugs (e.g. vemurafenib), but…

A P2X3-selective antagonist for chronic cough without taste effects. Camlipixant is an orally administered antagonist of the ATP-sensing P2X3 homotrimeric receptor ion channel, originated by AstraZeneca AB and assigned to the Canadian NEOMED Institute (now adMare), and developed by BELLUS Health (Canada), for the treatment of chronic cough. Chronic cough remains difficult to treat –…

Drug Hunter Reviewer Commentary. With over two decades of experience in neuroscience drug discovery, Drug Hunter reviewer Jake Schwarz says “mGluR2/3 agonists have been explored for schizophrenia, and agonists/PAMS could be tuned to give antagonist/NAM activity, but depression is a new indication. One of the more interesting depression approaches now is the use of ketamine,…

Overview. A common route of resistance to tuberculosis involves Mtb erm37 expression, which expresses an RNA methyltransferase that methylates the A2058 position of the 23S ribosome RNA, hindering macrolide antibiotic binding. The sequanamycins (SEQs) are a class of molecules that overcomes this resistance mechanism, primarily attributed to the change from a dimethylamine to a carbonyl/oxime,…

A KIT-selective, non-classical hinge binder-containing kinase inhibitor with best-in-class potential for the treatment of GIST. M4205 (IDRX-42) is a highly selective inhibitor of KIT, a class III receptor tyrosine kinase. KIT has been difficult to target effectively due to its high propensity for both mutations in the KIT gene, and secondary mutations within the ATP-binding…