BI-3231

Jump-started by a hit from an MS-based screen of the entire 1.1 million compound BI diversity screening deck, Thamm et al. report a best-in-class HSD17B13 inhibitor BI-3231, along with its matched negative control BI-0955. Both compounds are freely available on opnME directly from BI (https://www.opnme.com/molecules/hsd17b13-inhibitor-bi-3231). BI-3231 is very potent (IC < 1 nM in biochemical assay; IC50 = 12 nM in cellular assay) and inhibits both human and murine HSD17B13 through an uncompetitive binding mode that requires the presence of co-factor NAD+. BI-3231 is selective amongst other HSD17-family dehydrogenases via inference from the most closely related HSD17B11, although this has not been experimentally verified against other HSD17-family members or related hydroxysteroid dehydrogenases from other families. BI3231 does not inhibit 43/44 targets in the SafetyScreen44 panel (mostly GPCRs and ion channels) at 10 uM; it is a weak inhibitor of COX2 (50% inhibition at 10 uM). Note that the authors do not report off-target profiling against steroid receptors, notably AR, GR, PR, or ER; while BI-3231 is non-steroidal in structure, making it less likely to have off-target activity against these receptors, this could be a blind spot in the published selectivity panel. BI-3231 is suitable for PO dosing in mice and rats, and has reasonable oral bioavailability and moderate clearance (drive by Phase 2 glucuronidation of the phenol). Note that BI-3231 preferentially partitions to the liver, with drug exposures > 80-fold higher in the liver relative to other organs. Investigators hoping to inhibit HSD17B13 outside the liver should consider higher doses than those recommended in the table. BI-3231 only remains comfortably above the unbound Ki for 8 hours after an 50 umol/kg PO dose, so twice-a-day dosing could be required if constant target coverage is needed.