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Updated: May 30, 2026
Combining X-Ray Crystallography with Small Angle X-Ray Scattering to Model Unstructured Regions of Nsa1 from S. Cerevisiae
Published on: January 10, 2018
SAR by interligand nuclear overhauser effects (ILOEs) based discovery of acylsulfonamide compounds active against
Michele F Rega1, Bainan Wu, Jun Wei
1Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, California 92037, USA.
Abstract:
Overexpression of antiapoptotic members of the Bcl-2 family proteins, such as Bcl-x(L) and Mfl-1, has been shown to be involved in resistance to chemotherapeutic drugs in many forms of cancers. Recent efforts from the Abbott Laboratories resulted in the development of the acylsulfonamide compound and clinical candidate that targets selectively Bcl-2, Bcl-x(L), and Bcl-w while it is not active against Mcl-1 and Bfl-1. However, early clinical and preclinical studies suggest that pan-Bcl-2 antagonists, targeting simultaneously Mcl-1, Bcl-xL, and possibly all other four antiapoptotic Bcl-2 proteins, may result in more efficacious drugs. Here, following an NMR fragment-based approach, SAR by ILOEs, we report on compounds that exhibit nanomolar affinities for both Bcl-x(L) and Mcl-1 in vitro. We believe that these molecules can be used as useful starting point for the development of novel Bcl-2 antagonists, in particular targeting Mcl-1.
Insights
Novel compounds targeting antiapoptotic proteins Bcl-x(L) and Mcl-1 were developed using NMR fragment-based methods. These molecules show promise as starting points for new anti-cancer drugs, particularly those targeting Mcl-1.
Area of Science:
- Medicinal Chemistry
- Molecular Biology
- Oncology
Background:
- Overexpression of antiapoptotic Bcl-2 family proteins (e.g., Bcl-x(L), Mcl-1) contributes to cancer chemotherapy resistance.
- Selective Bcl-2 inhibitors exist but may lack efficacy compared to pan-Bcl-2 antagonists.
Purpose of the Study:
- To develop novel compounds targeting both Bcl-x(L) and Mcl-1.
- To identify starting points for more efficacious Bcl-2 antagonists.
Main Methods:
- Utilized Nuclear Magnetic Resonance (NMR) fragment-based approach.
- Employed Structure-Activity Relationship by Intrinsic Liabilities of Existing Scaffolds (SAR by ILOEs).
Main Results:
- Discovered compounds with nanomolar affinities for Bcl-x(L) in vitro.
- Identified compounds with nanomolar affinities for Mcl-1 in vitro.
Conclusions:
- The novel compounds represent promising starting points for developing new Bcl-2 antagonists.
- These molecules are particularly relevant for targeting Mcl-1 in cancer therapy.
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