Structure-based optimization of 1H-imidazole-2-carboxamides as Axl kinase inhibitors utilizing a Mer mutant surrogate
Walter Keung1, Amogh Boloor1, Jason Brown1
1Medicinal Chemistry, Takeda California, 10410 Science Center Drive, San Diego, CA 92121, United States.
Abstract:
Axl has been a target of interest in the oncology field for several years based on its role in various oncogenic processes. To date, no wild-type Axl crystal structure has been reported. Herein, we describe the structure-based optimization of a novel chemotype of Axl inhibitors, 1H-imidazole-2-carboxamide, using a mutated kinase homolog, Mer(I650M), as a crystallographic surrogate. Iterative optimization of the initial lead compound (1) led to compound (21), a selective and potent inhibitor of wild-type Axl. Compound (21) will serve as a useful compound for further in vivo studies.
Insights
Researchers developed a novel Axl inhibitor using structure-based drug design. This potent compound, identified through optimizing 1H-imidazole-2-carboxamides, shows promise for further oncology research.
Area of Science:
- Oncology
- Structural Biology
- Medicinal Chemistry
Background:
- Axl receptor tyrosine kinase is implicated in numerous oncogenic processes.
- No wild-type Axl crystal structure has been previously reported, hindering inhibitor design.
- Targeting Axl is a significant area of interest in cancer research.
Purpose of the Study:
- To describe the structure-based optimization of novel 1H-imidazole-2-carboxamide Axl inhibitors.
- To identify a potent and selective inhibitor of wild-type Axl.
- To develop a tool compound for future in vivo oncology studies.
Main Methods:
- Utilized a mutated kinase homolog, Mer(I650M), as a crystallographic surrogate for wild-type Axl.
- Employed structure-based drug design for iterative optimization of lead compounds.
- Screened and characterized novel chemotypes, specifically 1H-imidazole-2-carboxamides.
Main Results:
- Successfully optimized an initial lead compound (1) into a highly potent inhibitor (21).
- Compound (21) demonstrated selectivity for wild-type Axl.
- The Mer(I650M) surrogate facilitated structure-based optimization in the absence of wild-type Axl structure.
Conclusions:
- Developed a novel, potent, and selective inhibitor of wild-type Axl (compound 21).
- The structure-based optimization strategy using a surrogate kinase was effective.
- Compound (21) is a valuable tool for advancing in vivo studies in oncology.
