Drug Hunter Journal Club: April 2023

We couldn’t include everything in Molecules of the Month, but here’s a round-up of up of 16 additional molecules of potential interest that we didn’t have space for in April, including a highly selective caspase inhibitor from a non-catalytic cysteine, a GPR40 AgoPAM from BMS with activity on GLP-1, a few examples of both on- and off-target toxicities, and several clinical candidates.

1. Targeting a Caspase via a Non-Catalytic Cysteine

Arkin and Renslo labs, UCSF
J. Am. Chem. Soc. Apr. 27, 2023
https://pubs.acs.org/doi/10.1021/jacs.2c12240

compound 3a
caspase-6 IC50 = 8 nM

If you’re like many scientists who haven’t checked JACS every morning since leaving academia, you may have missed this interesting case study from Michelle Arkin and Adam Renslo’s teams at UCSF. Starting from hits identified from a disulfide compound library, potent, irreversible inhibitors and chemoproteomic probes for caspase-6, an understudied caspase isoform, were discovered. Selectivity has been historically challenging to achieve within the caspase family of proteases. These tools show remarkable selectivity over other caspase family members and high proteome selectivity overall, enabling rigorous interrogation of caspase-6's role in a range of disease settings.