title: Structure-based design of 3-carboxy-substituted 1,2,3,4-tetrahydroquinolines as inhibitors of myeloid cell leukemia-1 (Mcl-1).
abstract: 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 Ki 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.
authors.affiliation: Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 N. Pine St., Baltimore, MD 21201, USA. sfletcher@rx.umaryland.edu.
authors.forename: L
authors.initials: L
authors.lastname: Chen
authors.forename: P T
authors.initials: PT
authors.lastname: Wilder
authors.forename: B
authors.initials: B
authors.lastname: Drennen
authors.forename: J
authors.initials: J
authors.lastname: Tran
authors.forename: B M
authors.initials: BM
authors.lastname: Roth
authors.forename: K
authors.initials: K
authors.lastname: Chesko
authors.forename: P
authors.initials: P
authors.lastname: Shapiro
authors.forename: S
authors.initials: S
authors.lastname: Fletcher
mesh_terms: D015195:Drug Design; D062105:Molecular Docking Simulation; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D011487:Protein Conformation; D011804:Quinolines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D064549:Myeloid Cell Leukemia Sequence 1 Protein; D011804:Quinolines; C542964:1,2,3,4-tetrahydroquinoline