Novel soluble myeloid cell leukemia sequence 1 (Mcl-1) inhibitor (E,E)-2-(benzylaminocarbonyl)-3-styrylacrylonitrile (4g) developed using a fragment-based approach

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).

A series of new Mcl-1 inhibitors were synthesized. 4g binds Mcl-1 with a Ki value of 0.16 μM, and selectively induces apoptosis in Mcl-1-dependent NCI-H23 cells (IC50 = 0.38 μM).Figure optionsDownload as PowerPoint slideHighlights
► A novel Mcl-1 inhibitor 4g was synthesized using a fragment-based approach.
► Mcl-1 protein NMR was employed to identify the binding mode of 4g with Mcl-1.
► 4g selectively induced apoptosis in Mcl-1-dependent cancer cells.
► A prediction map for Mcl-1 inhibitors was constructed.