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Updated: Mar 25, 2026
NMR-Based Fragment Screening in a Minimum Sample but Maximum Automation Mode
Published on: June 4, 2021
Discovery of 2-Indole-acylsulfonamide Myeloid Cell Leukemia 1 (Mcl-1) Inhibitors Using Fragment-Based Methods
Nicholas F Pelz1, Zhiguo Bian1, Bin Zhao1
1Department of Biochemistry, Vanderbilt University School of Medicine , 2215 Garland Avenue, 607 Light Hall, Nashville, Tennessee 37232-0146, United States.
Abstract:
Myeloid cell leukemia-1 (Mcl-1) is a member of the Bcl-2 family of proteins responsible for the regulation of programmed cell death. Amplification of Mcl-1 is a common genetic aberration in human cancer whose overexpression contributes to the evasion of apoptosis and is one of the major resistance mechanisms for many chemotherapies. Mcl-1 mediates its effects primarily through interactions with pro-apoptotic BH3 containing proteins that achieve high affinity for the target by utilizing four hydrophobic pockets in its binding groove. Here we describe the discovery of Mcl-1 inhibitors using fragment-based methods and structure-based design. These novel inhibitors exhibit low nanomolar binding affinities to Mcl-1 and >500-fold selectivity over Bcl-xL. X-ray structures of lead Mcl-1 inhibitors when complexed to Mcl-1 provided detailed information on how these small-molecules bind to the target and were used extensively to guide compound optimization.
Insights
Researchers discovered novel inhibitors targeting Myeloid cell leukemia-1 (Mcl-1), a protein implicated in cancer and chemotherapy resistance. These potent inhibitors show high selectivity, offering a promising new avenue for cancer treatment development.
Area of Science:
- Biochemistry
- Molecular Biology
- Medicinal Chemistry
Background:
- Myeloid cell leukemia-1 (Mcl-1) is a key regulator of apoptosis and a frequent target in cancer therapy.
- Mcl-1 overexpression drives cancer progression and confers resistance to chemotherapy by inhibiting programmed cell death.
- Mcl-1 interacts with pro-apoptotic proteins via hydrophobic pockets in its binding groove.
Purpose of the Study:
- To discover and characterize novel small-molecule inhibitors of Mcl-1.
- To develop potent and selective Mcl-1 inhibitors for potential therapeutic applications.
- To elucidate the binding interactions of novel inhibitors with Mcl-1 through structural analysis.
Main Methods:
- Fragment-based drug discovery approaches.
- Structure-based drug design and optimization.
- X-ray crystallography to determine inhibitor-Mcl-1 complex structures.
Main Results:
- Identification of novel Mcl-1 inhibitors with low nanomolar binding affinities.
- Achieved >500-fold selectivity for Mcl-1 over Bcl-xL.
- Detailed structural insights into small-molecule binding to Mcl-1, guiding optimization.
Conclusions:
- Novel fragment-derived inhibitors effectively target Mcl-1.
- High selectivity and potency achieved through structure-based design.
- These Mcl-1 inhibitors represent promising candidates for overcoming chemotherapy resistance in cancer.
