Interdiction at a protein-protein interface: MCL-1 inhibitors for oncology

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Cancer cells evade apoptosis, a programmed cell death process.
• Myeloid cell leukemia-1 (MCL-1) is an anti-apoptotic protein in the BCL-2 family, crucial for cancer cell survival and treatment resistance.
• The balance of pro- and anti-apoptotic protein interactions regulates cell death.

Purpose of the Study:

• To review the current state of MCL-1 inhibitors.
• To highlight the discovery and medicinal chemistry of MCL-1 inhibitors.
• To emphasize structure-based drug design and biological evaluations of these inhibitors.

Main Methods:

• Review of recent literature on MCL-1 inhibitors.
• Focus on structure-based drug design (SBDD) strategies.
• Analysis of biological evaluations of small molecule BH3 mimetics targeting MCL-1.

Main Results:

• Significant progress in developing small molecule BH3 mimetics targeting MCL-1.
• Multiple MCL-1 inhibitor candidates have entered clinical trials.
• Structure-based drug design has been instrumental in optimizing inhibitor potency and selectivity.

Conclusions:

• MCL-1 inhibitors represent a promising therapeutic strategy in oncology.
• Targeting MCL-1 protein-protein interactions offers a viable approach to overcome cancer treatment resistance.
• Continued research in medicinal chemistry and SBDD is vital for advancing MCL-1 targeted therapies.