Structure-based design of 3-carboxy-substituted 1,2,3,4-tetrahydroquinolines as inhibitors of myeloid cell leukemia-1 (Mcl-1)

• Published in: Organic & biomolecular chemistry 2016-01, Vol.14 (24), p.555-551
• Main Authors: Chen, L, Wilder, P. T, Drennen, B, Tran, J, Roth, B. M, Chesko, K, Shapiro, P, Fletcher, S
• Format: Article
• Language: English
• Subjects: Drug Design; Molecular Docking Simulation; Myeloid Cell Leukemia Sequence 1 Protein - antagonists & inhibitors; Myeloid Cell Leukemia Sequence 1 Protein - chemistry; Myeloid Cell Leukemia Sequence 1 Protein - metabolism; Protein Conformation; Quinolines - chemistry; Quinolines - metabolism; Quinolines - pharmacology; Structure-Activity Relationship
• ISSN: 1477-0520; 1477-0539
• DOI: 10.1039/c5ob02063h

Mcl-1 has recently emerged as an attractive target to expand the armamentarium in the war on cancer. Using structure-based design, 3-carboxy-substituted 1,2,3,4-tetrahydroquinolines were developed as a new chemotype to inhibit the Mcl-1 oncoprotein. The most potent compound inhibited Mcl-1 with a K i of 120 nM, as determined by a fluorescence polarization competition assay. Direct binding was confirmed by 2D 1 H- 15 N HSQC NMR spectroscopy with 15 N-Mcl-1, which indicated that interactions with R263 and T266, and occupation of the p2 pocket are likely responsible for the potent binding affinity. The short and facile synthetic chemistry to access target molecules is expected to mediate lead optimization. A novel Mcl-1 inhibitor chemotype based on a tetrahydroquinoline carboxylic acid was developed utilizing structure-based design, which was subsequently validated by a fluorescence polarization competition assay and HSQC NMR analysis.