The anti-apoptotic myeloid cell leukemia protein Mcl-1, a member of the Bcl-2 family proteins, has emerged as a promising therapeutic target.  Using structure-based design, a new series of sulfonamido-1-hydroxynaphthalene Mcl-1 inhibitors were synthesized based on the lead compound identified from high throughput screening. The initial structure-activity relationship was established using a competitive fluorescent polarization and surface plasmon resonance based assays. The docking model predicted that this class of compounds binds to the BH3 binding site in Mcl-1 protein mimicking two conserved hydrophobic residues from BH3 binding motif. This model was confirmed by using HSQC-NMR spectroscopy demonstrating that this class of compounds binds to the same BH3 domain of Mcl-1 as the Bim BH3 peptide. The most potent analogues inhibit cell growth and induce apoptosis in different cancer cells, including lymphoma, melanoma and pancreatic cancer cells. These findings provide promise for further chemical modifications and development of potent small-molecule Mcl-1 inhibitors.

Design, synthesis and biological evaluation of substituted sulfonamido-1-hydroxynaphthalene compounds as novel small-molecule Mcl-1 inhibitors

243rd National Meeting (2012)

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