Fragment-based design, synthesis, and biological evaluation of N-substituted-5-(4-isopropylthiophenol)-2-hydroxynicotinamide derivatives as novel Mcl-1 inhibitors

We have previously reported a nanomolar inhibitor of antiapoptotic Mcl-1 protein, 3-thiomorpholin-8-oxo-8H-acenaphtho [1,2-b] pyrrole-9-carbonitrile (S1). S1 plays its function by binding to the BH3 groove of Mcl-1. Basing on this spacial structural characteristic, we developed a novel class of Mcl-1 inhibitor using fragment-based drug discovery approach. By dissecting S1, we identified the compound 4 with a 2-hydroxypyridine core as the starting fragment. In the following molecular growth, we used the ligand efficiency evaluation and fit quality score to assess the fragments. A novel potent compound, N-benzyl-5-(4-isopropylthiophenol)-2-hydroxyl nicotinamide (12c), which binds Mcl-1 with an IC50 value of 54 nM was obtained. Compound 12c demonstrated a better aqueous solubility than S1.

A nearly linear relationship exists between ΔG and HAC over the compounds 4, 6e, 6g, and 12c, demonstrating a reasonable lead optimization route in our fragment-based drug design.Figure optionsDownload as PowerPoint slideHighlights
► A novel class of small-molecule inhibitors of Mcl-1 were developed through the fragment-based drug discovery approach.
► Fragment evolution was guided by the analysis of ligand efficiency evaluation and fit quality score.
► A potent inhibitor 12c binding to Mcl-1 with an IC50 value of 56 nM was obtained.