Discovery and structure-activity relationship studies of novel Bcl-2/Mcl-1 dual inhibitors with indole scaffold

Area of Science:

• Medicinal Chemistry
• Molecular Biology
• Cancer Research

Background:

• Bcl-2 family proteins, particularly Bcl-2 and Mcl-1, are frequently overexpressed in tumors.
• This overexpression contributes to apoptosis evasion and chemotherapy resistance, making them key therapeutic targets.

Purpose of the Study:

• To identify and optimize novel small molecules as dual inhibitors of Bcl-2 and Mcl-1.
• To evaluate the binding affinities, structure-activity relationships, and anti-cancer efficacy of these novel compounds.

Main Methods:

• Optimization of a hit compound using an indole scaffold.
• Systematic structure modifications of hydrophobic fragments, side chains, and benzoic acid moieties.
• Assessment of binding affinities to Bcl-2, Mcl-1, and Bcl-X_L.
• Apoptosis induction studies in HL-60 cancer cells.

Main Results:

• Identification of novel Bcl-2/Mcl-1 dual inhibitors based on an indole scaffold.
• Compound 12f demonstrated sub-micromolar binding affinities for Bcl-2 and Mcl-1, with no significant binding to Bcl-X_L.
• Compound 12f dose-dependently induced apoptosis in HL-60 cells, confirming its mechanism of action.

Conclusions:

• Compound 12f is a potent and selective Bcl-2/Mcl-1 dual inhibitor.
• The developed indole-based inhibitors warrant further investigation for cancer therapy.