title: Fragment-Based Design, Synthesis, and Biological Evaluation of 1-Substituted-indole-2-carboxylic Acids as Selective Mcl-1 Inhibitors.
abstract: Based on a known selective Mcl-1 inhibitor, 6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1H-indole-2-carboxylic acid, we applied a fragment-based approach to obtain new molecules that extended into the p1 pocket of the BH3 groove and then exhibited binding selectivity for the Mcl-1 over the Bcl-2 protein. After we deconstructed the 1H-indole-2-carboxylic acid from the parental molecule, a benzenesulfonyl was substituted at the 1-position to adopt a geometry preferred for accessing the p1 pocket according to the binding mode of the parental molecule identified by X-ray crystallography. A linear relationship between the free energy of ligand binding (ΔG) and the count of non-hydrogen heavy atoms (HAC) was maintained during the molecular growing to occupy the p1 pocket. Finally, we not only obtained compound 12 with a 7.5-fold selectivity to Mcl-1 (Ki= 0.48 µM by fluorescence polarization) over Bcl-2 (Ki= 3.6 µM), but also provided evidence that additional occupation of the p1 pocket is more favorable for Mcl-1 than for Bcl-2 binding, and contributes more to Mcl-1 inhibition than occupation of the p2 pocket. Compound 12 exhibited a selective killing ability on Mcl-1-dependent cancer cells.
authors.affiliation: State Key Laboratory of Fine Chemicals, School of Chemistry, Dalian University of Technology, Dalian, People's Republic of China.
authors.forename: Ziqian
authors.initials: Z
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Fine Chemicals, School of Chemistry, Dalian University of Technology, Dalian, People's Republic of China.
authors.forename: Wenjie
authors.initials: W
authors.lastname: Xu
authors.affiliation: School of Life Science and Technology, Dalian University of Technology, Dalian, People's Republic of China.
authors.forename: Ting
authors.initials: T
authors.lastname: Song
authors.affiliation: School of Life Science and Technology, Dalian University of Technology, Dalian, People's Republic of China.
authors.forename: Zongwei
authors.initials: Z
authors.lastname: Guo
authors.affiliation: State Key Laboratory of Fine Chemicals, School of Chemistry, Dalian University of Technology, Dalian, People's Republic of China.
authors.forename: Lu
authors.initials: L
authors.lastname: Liu
authors.affiliation: School of Life Science and Technology, Dalian University of Technology, Dalian, People's Republic of China.
authors.forename: Yudan
authors.initials: Y
authors.lastname: Fan
authors.affiliation: State Key Laboratory of Fine Chemicals, School of Chemistry, Dalian University of Technology, Dalian, People's Republic of China.
authors.forename: Anhui
authors.initials: A
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Fine Chemicals, School of Chemistry, Dalian University of Technology, Dalian, People's Republic of China.
authors.forename: Zhichao
authors.initials: Z
authors.lastname: Zhang
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001667:Binding, Competitive; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000037:antagonists & inhibitors*; D011485:Protein Binding; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2
keywords: Fragment-based drug design; Ligand efficiency; Mcl-1 inhibitor; Selective; p1 pocket