Discovery of tricyclic indoles that potently inhibit Mcl-1 using fragment-based methods and structure-based design

Area of Science:

• Oncology
• Molecular Biology
• Medicinal Chemistry

Background:

• Myeloid cell leukemia-1 (Mcl-1) is an antiapoptotic protein frequently overexpressed in various cancers.
• Mcl-1 overexpression promotes cancer cell survival and chemoresistance, representing a significant therapeutic challenge.

Purpose of the Study:

• To identify novel small-molecule inhibitors targeting Mcl-1.
• To characterize the binding affinity and selectivity of newly discovered inhibitors.
• To elucidate the binding mode of these inhibitors through structural analysis.

Main Methods:

• NMR-based screening of a large fragment library to identify Mcl-1 binders.
• Medicinal chemistry optimization of initial hit compounds.
• Biochemical assays to determine binding affinity (nM) and selectivity (>1700-fold vs. Bcl-xL, >100-fold vs. Bcl-2).
• X-ray crystallography to obtain co-complex structures with Mcl-1.

Main Results:

• Discovery of potent tricyclic 2-indole carboxylic acid derivatives as Mcl-1 inhibitors.
• Achieved single-digit nanomolar binding affinity for Mcl-1.
• Demonstrated high selectivity over related antiapoptotic proteins Bcl-xL and Bcl-2.
• X-ray crystallography provided detailed insights into the small-molecule binding interactions with Mcl-1.

Conclusions:

• Tricyclic 2-indole carboxylic acids represent a promising class of Mcl-1 inhibitors.
• The identified compounds exhibit potent and selective inhibition of Mcl-1.
• Structural information guides further optimization for potential cancer therapeutics targeting Mcl-1.