A selective JAK-1 inhibitor; plus deep learning methods to explore new protein designs and more

A team led by Benjamin Cravatt at The Scripps Research Institute and Matthew Patricelli, head of early discovery at Vividion Therapeutics Inc., developed a compound, VVD-118313, to selectively inhibit JAK-1. The authors used chemical proteomics to find a druggable allosteric cysteine present in the non-catalytic pseudokinase domains of JAK-1 and TYK2, but absent from JAK-2 or JAK-3. “Electrophilic compounds selectively engaging this site block JAK-1-dependent trans-phosphorylation and cytokine signaling, while appearing to act largely as ‘silent’ ligands for TYK2,” the authors wrote in Nature Chemical Biology. Bayer AG (Xetra:BAYN) acquired Vividion in August 2021.

It’s been a challenge to engineer selective inhibitors against JAKs that don’t cross-react with the other three members of the family due to the 98% homology in their active sites, causing companies such as  Bristol Myers Squibb Co. (NYSE:BMY) and Nimbus Therapeutics LLC to take an allosteric approach to developing JAK inhibitors with isoform selectivity...