Recent advances of small-molecule Mcl-1 inhibitors or degraders as promising anti-cancer agents (2018-present)

Area of Science:

• Molecular Biology
• Cancer Biology
• Drug Discovery

Background:

• The B-cell lymphoma protein 2 (Bcl-2) family regulates apoptosis, with myeloid cell leukemia-1 (Mcl-1) being crucial for mitochondrial function.
• Mcl-1 overexpression is linked to various hematological malignancies and solid tumors, correlating with poor prognosis and chemoresistance.
• Mcl-1 represents a significant therapeutic target in oncology.

Purpose of the Study:

• To review recent advancements in small-molecule Mcl-1 inhibitors and degraders as anti-cancer agents from 2018 to the present.
• To provide insights into structure-activity relationships (SARs) of these compounds.
• To elucidate co-crystal structures of potent Mcl-1 inhibitors with the Mcl-1 protein.

Main Methods:

• Literature review of scientific publications from 2018 to the present.
• Analysis of small-molecule inhibitors and degraders targeting Mcl-1, categorized by core scaffolds.
• Examination of reported structure-activity relationships (SARs).
• Review of co-crystal structures of Mcl-1 inhibitors bound to the Mcl-1 protein.

Main Results:

• Summary of novel small-molecule Mcl-1 inhibitors and degraders developed.
• Detailed SARs for various compound classes.
• Elucidation of structural basis for Mcl-1 inhibition through co-crystal structures.

Conclusions:

• Small-molecule Mcl-1 inhibitors and degraders show significant promise as anti-cancer agents.
• Understanding SARs and co-crystal structures aids in designing more effective Mcl-1-targeted therapies.
• This review provides valuable insights for medicinal chemists in developing next-generation Mcl-1-targeting drugs.