Discovery and structure-activity relationship studies of N-substituted indole derivatives as novel Mcl-1 inhibitors

Bioorg Med Chem Lett. 2017 May 1;27(9):1943-1948. doi: 10.1016/j.bmcl.2017.03.028. Epub 2017 Mar 16.

Abstract

Myeloid cell leukemia-1 (Mcl-1) is an important antiapoptotic protein functioning through protein-protein interactions. We discovered LSL-A6 (2-((2-carbamoyl-1-(3-(4-methoxyphenoxy)propyl)-1H-indol-6-yl)oxy)acetic acid) with a novel N-substituted indole scaffold to interfere Mcl-1 binding as a novel Mcl-1 inhibitor. Molecular modeling indicated that this compound binds with Mcl-1 by interaction with P2 and R263 hot-spots. Structure modification focused on several moieties including indole core, hydrophobic tail and acidic chain were conducted and structure-activity relationship was analyzed. The most potent compound 24d which exhibited Ki value of 110nM for interfering Mcl-1 binding was obtained after hit-to-lead modification.

Keywords: Apoptosis; Bcl-2; Mcl-1; Structure-based design.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Drug Design
  • Humans
  • Indoles / chemistry*
  • Indoles / pharmacology*
  • Molecular Docking Simulation
  • Myeloid Cell Leukemia Sequence 1 Protein / antagonists & inhibitors*
  • Myeloid Cell Leukemia Sequence 1 Protein / metabolism
  • Protein Binding / drug effects
  • Structure-Activity Relationship

Substances

  • Indoles
  • MCL1 protein, human
  • Myeloid Cell Leukemia Sequence 1 Protein