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Updated: Jun 28, 2025
Pre-clinical Evaluation of Tyrosine Kinase Inhibitors for Treatment of Acute Leukemia
Published on: September 18, 2013
Targeting Myeloid Leukemia-1 in Cancer Therapy: Advances and Directions
Hongguang Deng1, Yu Han1, Liang Liu1
1Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China.
Abstract:
As a tripartite cell death switch, B-cell lymphoma protein 2 (Bcl-2) family members precisely regulate the endogenous apoptosis pathway in response to various cell signal stresses through protein-protein interactions. Myeloid leukemia-1 (Mcl-1), a key anti-apoptotic Bcl-2 family member, is positioned downstream in the endogenous apoptotic pathway and plays a central role in regulating mitochondrial function. Mcl-1 is highly expressed in a variety of hematological malignancies and solid tumors, contributing to tumorigenesis, poor prognosis, and chemoresistance, making it an attractive target for cancer treatment. This Perspective aims to discuss the mechanism by which Mcl-1 regulates apoptosis and non-apoptotic functions in cancer cells and to outline the discovery and optimization process of potent Mcl-1 modulators. In addition, we summarize the structural characteristics of potent inhibitors that bind to Mcl-1 through multiple co-crystal structures and analyze the cardiotoxicity caused by current Mcl-1 inhibitors, providing prospects for rational targeting of Mcl-1.
Insights
Myeloid leukemia-1 (Mcl-1) is a key regulator of apoptosis highly expressed in cancers. Targeting Mcl-1 offers a promising strategy for cancer treatment, though careful consideration of cardiotoxicity is needed.
Area of Science:
- Molecular Biology
- Cancer Biology
- Drug Discovery
Background:
- B-cell lymphoma protein 2 (Bcl-2) family members regulate apoptosis via protein-protein interactions.
- Myeloid leukemia-1 (Mcl-1), an anti-apoptotic protein, is crucial for mitochondrial function and highly expressed in various cancers.
- Mcl-1 overexpression contributes to tumorigenesis, poor prognosis, and chemoresistance.
Purpose of the Study:
- To discuss Mcl-1's role in apoptosis and non-apoptotic functions in cancer.
- To outline the discovery and optimization of Mcl-1 modulators.
- To analyze Mcl-1 inhibitor structural characteristics and cardiotoxicity.
Main Methods:
- Review of literature on Mcl-1 function and regulation.
- Analysis of co-crystal structures of Mcl-1 inhibitors.
- Evaluation of cardiotoxicity data for Mcl-1 inhibitors.
Main Results:
- Mcl-1 regulates both apoptotic and non-apoptotic pathways in cancer cells.
- Potent Mcl-1 inhibitors have been discovered and optimized, with structural insights provided.
- Current Mcl-1 inhibitors exhibit cardiotoxicity, necessitating further research.
Conclusions:
- Mcl-1 is a critical target for cancer therapy.
- Understanding Mcl-1's mechanisms and inhibitor structures is key to developing effective treatments.
- Rational targeting of Mcl-1 requires addressing associated cardiotoxicity for improved therapeutic outcomes.
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