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Discovery of A-1331852, a First-in-Class, Potent, and Orally-Bioavailable BCL-XL Inhibitor
Le Wang1, George A Doherty1, Andrew S Judd1
1AbbVie Inc., 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
ACS Medicinal Chemistry Letters
|October 16, 2020
Summary
Researchers discovered A-1331852, a novel oral inhibitor targeting BCL-XL. This selective drug induces apoptosis in cancer cells dependent on BCL-XL, offering a promising new avenue for cancer therapy.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- BCL-XL is a key regulator of apoptosis.
- Dysregulation of BCL-XL is implicated in various cancers.
- Targeting BCL-XL offers a therapeutic strategy for cancer treatment.
Purpose of the Study:
- To describe the discovery of A-1331852, a novel BCL-XL inhibitor.
- To detail the structure-based drug design process for A-1331852.
- To establish A-1331852 as a tool for BCL-2 family protein research.
Main Methods:
- Structure-based drug design was employed.
- Re-engineering of a prior BCL-XL inhibitor (A-1155463).
- Incorporation of rigidified pharmacophore and sp3-rich moieties.
Main Results:
- Discovery of A-1331852, an orally active BCL-XL inhibitor.
- A-1331852 selectively and potently induces apoptosis in BCL-XL-dependent tumor cells.
- The molecule demonstrates productive interactions within the BCL-XL P4 pocket.
Conclusions:
- A-1331852 is a first-in-class inhibitor with therapeutic potential.
- A-1331852 serves as a valuable tool for studying BCL-2 family biology.
- The molecule represents a promising starting point for drug discovery programs.
