This month features some remarkable molecules including an allosteric pan-mutant isoform-selective PI3Kα inhibitor, a potentially best-in-class CNS-penetrant PARP1 inhibitor and trapper, and a photoswitchable HCN blocker to treat pigmentosa and choroideremia. Additionally, the IRAK4 degrader, KT-474, makes the top of the list this month with positive results from the molecule’s Ph. I trials for AD and HS.
You can read Drug Hunter’s full case study on KT-474 here and stay tuned for more detailed case studies on these fascinating molecules. In the meantime, you can check out the recent articles about the following here:
KT-474 – An oral IRAK4 degrader in Phase II for hidradenitis suppurativa (HS) and atopic dermatitis (AD) that was discovered by Kymera Therapeutics and is currently being developed by Sanofi (renamed as SAR444656).
RLY-2608 – An oral allosteric pan-mutant isoform-selective PI3Kα inhibitor that was discovered using MD modeling and cryo-EM to identify allosteric networks and opportunities for small molecules, followed by DEL screening, by D.E. Shaw and Relay Therapeutics.
LY3522348 – A selective dual hKHK-C/A inhibitor in a Phase I healthy volunteer study from Eli Lilly.
AZD9574 – An oral, best-in-class CNS-penetrant PARP1 inhibitor and trapper in Phase I/II trials for advanced cancer treatment from AstraZeneca.
pelcitoclax - A dual BCL-2/xL inhibitor prodrug in Phase I/II for NHL being developed by Ascentage Pharma.
KB-0742 – A selective CDK9 inhibitor in Phase I/II trials for R/R solid tumors and NHL discovered through a small molecule microarray (SMM) screen being developed by Kronos Bio.
AM-2-19 - An ergosterol-extracting polyene antifungal that was discovered through modifications to the amphotericin B toxin by chemists at the University of Illinois Urbana-Champaign and University of Wisconsin-Madison, and is currently in Phase I clinical trials by Sfunga Therapeutics (renamed SF001)
KIO-301 – A photoswitchable HCN channel blocker with positive initial results from a Phase I/II for retinitis pigmentosa and choroideremia study that is being developed by KIORA Therapeutics. KIO-301 was acquired from Bayon, a company associated with UC Berkeley.
FX-909 – A selective covalent PPARG inhibitor, discovered from optimization of a prior covalent inverse agonist by Flare Therapeutics, is in Phase I for solid tumors and urothelial carcinoma.
AMG487 – The only CXCR3 antagonist to go to clinical trials has had its CXCR3 complex structure solved, providing insight into its mechanism of antagonism.