Discovery of a potent and selective Axl inhibitor in preclinical model
Satoshi Inoue1, Yoshinobu Yamane1, Shuntaro Tsukamoto2
1Medicinal Chemistry, Tsukuba Research Laboratories, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba-shi, Ibaraki 300-2635, Japan.
Abstract:
Axl and Mer are a members of the TAM (Tyro3-Axl-Mer) family of receptor tyrosine kinases, which, when activated, can promote tumor cell survival, proliferation, migration, invasion, angiogenesis, and tumor-host interactions. Chronic inhibition of Mer leads to retinal toxicity in mice. Therefore, successful development of an Axl targeting agent requires ensuring that it is safe for prolonged treatment. Here, to clarify whether enzyme inhibition of Mer by a small molecule leads to retinal toxicity in mice, we designed and synthesized Axl/Mer inhibitors and Axl-selective inhibitors. We identified an Axl/Mer dual inhibitor 28a, which showed retinal toxicity at a dose of 100 mg/kg in mice. Subsequent derivatization of a pyridine derivative led to the discovery of a pyrimidine derivative, 33g, which selectively inhibited the activity of Axl over Mer without retinal toxicity at a dose of 100 mg/kg in mice. Additionally, the compound displayed in vivo anti-tumor effects without influencing body weight in a Ba/F3-Axl isogenic subcutaneous model.
Insights
Researchers developed a novel Axl-selective inhibitor that avoids Mer-related retinal toxicity seen with dual Axl/Mer inhibitors. This compound shows promising anti-tumor effects without adverse effects, enabling safer, prolonged cancer treatment.
Area of Science:
- Oncology
- Pharmacology
- Toxicology
Background:
- The TAM receptor tyrosine kinase family, including Axl and Mer, plays a role in tumor progression and host interactions.
- Chronic Mer inhibition in mice has been linked to retinal toxicity, posing a challenge for developing safe Axl-targeting agents.
Purpose of the Study:
- To investigate whether small molecule enzyme inhibition of Mer causes retinal toxicity.
- To design and synthesize novel Axl/Mer inhibitors and Axl-selective inhibitors for cancer therapy development.
Main Methods:
- Synthesis of Axl/Mer dual inhibitors and Axl-selective inhibitors.
- Evaluation of retinal toxicity in mice at a dose of 100 mg/kg.
- Assessment of in vivo anti-tumor efficacy in a Ba/F3-Axl isogenic subcutaneous model.
Main Results:
- An Axl/Mer dual inhibitor (28a) demonstrated retinal toxicity in mice at 100 mg/kg.
- A novel pyrimidine derivative (33g) selectively inhibited Axl over Mer without causing retinal toxicity at 100 mg/kg.
- Compound 33g exhibited in vivo anti-tumor activity without affecting body weight.
Conclusions:
- Selective Axl inhibition is achievable without the retinal toxicity associated with Mer inhibition.
- The Axl-selective inhibitor 33g represents a potentially safer therapeutic candidate for prolonged cancer treatment.
- Further development of Axl-targeting agents can proceed with a focus on selectivity to mitigate toxicity concerns.
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