molecules of the month

The Chinook LDHA/GO dual inhibitor, compound 7, targets two clinically validated targets for hyperoxaluria, a rare genetic disorder that results in oxalate overproduction and sometimes kidney failure. GO is encoded by HAO1, the target of recently approved siRNA drug lumasiran, and LDHA is selectively targeted by Dicerna’s nidosiran. The authors aimed to make a small molecule that could target both enzymes simultaneously, and used a structure-based approach to fuse GO and LDHA inhibitors into compounds with in vitro activity and confirmed binding to both enzymes by X-ray crystallography. Unfortunately, the molecule doesn’t demonstrate activity in vivo due to low oral exposure, a property that is challenging to optimize with a large diacid. Also disappointingly, in vitro, dual inhibition of LDHA/GO doesn’t appear to have…