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Updated: Nov 1, 2025
Protein WISDOM: A Workbench for In silico De novo Design of BioMolecules
Published on: July 25, 2013
Structure-Based Design of A-1293102, a Potent and Selective BCL-XL Inhibitor
Zhi-Fu Tao1, Xilu Wang1, Jun Chen1
1AbbVie Inc., 1 North Waukegan Rd, North Chicago, Illinois 60064, United States.
Abstract:
BCL-XL, an antiapoptotic member of the BCL-2 family of proteins, drives tumor survival and maintenance and thus represents a key target for cancer treatment. Herein we report the rational design of a novel series of selective BCL-XL inhibitors exemplified by A-1293102. This molecule contains structural elements of selective BCL-XL inhibitor A-1155463 and the dual BCL-XL/BCL-2 inhibitors ABT-737 and navitoclax, while representing a distinct pharmacophore as assessed by an objective cheminformatic evaluation. A-1293102 exhibited picomolar binding affinity to BCL-XL and both efficiently and selectively killed BCL-XL-dependent tumor cells. X-ray crystallographic analysis demonstrated a key hydrogen bonding network in the P2 binding pocket of BCL-XL, while the bent-back moiety achieved efficient occupancy of the P4 pocket in a manner similar to that of navitoclax. A-1293102 represents one of the few distinct structural series of selective BCL-XL inhibitors, and thus serves as a useful tool for biological studies as well as a lead compound for further optimization.
Insights
Researchers designed a novel BCL-XL inhibitor, A-1293102, which selectively targets and kills cancer cells dependent on BCL-XL for survival. This compound offers a new structural class for cancer therapy research.
Area of Science:
- Oncology
- Molecular Biology
- Medicinal Chemistry
Background:
- The antiapoptotic protein BCL-XL is crucial for cancer cell survival and a key therapeutic target.
- Existing inhibitors like ABT-737 and navitoclax offer insights but distinct pharmacophores are needed.
Purpose of the Study:
- To rationally design and characterize a novel series of selective BCL-XL inhibitors.
- To evaluate the anti-cancer potential of a lead compound, A-1293102.
Main Methods:
- Cheminformatic evaluation to assess pharmacophore distinctness.
- Biochemical assays to determine binding affinity (picomolar).
- Cell-based assays to evaluate tumor cell killing efficacy.
- X-ray crystallography to elucidate binding interactions.
Main Results:
- A-1293102 demonstrated picomolar binding affinity for BCL-XL.
- The compound selectively killed BCL-XL-dependent tumor cells.
- X-ray crystallography revealed key interactions within the BCL-XL binding pockets (P2 and P4).
Conclusions:
- A-1293102 represents a distinct structural class of selective BCL-XL inhibitors.
- This novel inhibitor serves as a valuable tool for biological studies.
- A-1293102 is a promising lead compound for further cancer therapeutic development.
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