Abstract
Based on a known nanomolar Bcl-2 homology domain 3 (BH3) mimetic 3-thiomorpholin-8-oxo-8H-acenaphtho[1,2-b] pyrrole-9-carbonitrile (S1, MW: 331), we applied a fragment-based approach to obtain BH3 mimetics with improved affinity and improved solubility in a water–ethanol (9:1) cosolvent. After the deconstruction of 1 (S1), we obtained fragment cyanoacetamide (4), which was determined to be a ligand efficiency (LE) hot part. After a rational optimization through fragment evolution beginning with fragment 4, a smaller Mcl-1 inhibitor (E,E)-2-(benzylaminocarbonyl)-3-styrylacrylonitrile (4g, MW: 288) with a 6-fold increase in affinity compared to 1 was obtained, as predicted by our optimization curve and identified by Mcl-1 protein nuclear magnetic resonance (NMR).
Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
