Electrophile-first screen yields covalent aminothiazole inhibitors of the E2 enzyme UBE2D2
- An electrophile-first screen, combined with X-ray crystallography, found a covalent hit that engages two cysteines (C85 and C111) of UBE2D2.
- Structure-guided SAR on the amide and ester groups removed binding to C111 while improving engagement of C85.
- The optimized analog inhibited UBE2D2 activity in vitro and suppressed proliferation of A549 lung cancer cells.
💡 Points
E2s have long been written off as undruggable, so seeing a crystal-supported covalent series is a real step. The interesting design move is dialing out the second cysteine, which is exactly what you need before calling anything a probe. I'd now ask how it behaves across other UBE2D family members, since the active-site cysteine is conserved and selectivity will be the hard part.