Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 64, Issue 7, Pages 3956-3975Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.0c02093
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Funding
- Science and Technology Commission of Shanghai Municipality [18431907100]
- National Science & Technology Major Project Key New Drug Creation and Manufacturing Program of China [2018ZX09711002-011-016]
- Natural Science Foundation of China for Innovation Research Group [81821005]
- Collaborative Innovation Cluster Project of Shanghai Municipal Commission of Health and Family Planning [2020CXJQ02]
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Compound 13c is a highly potent and orally bioavailable Axl inhibitor, showing inhibition of both Axl superfamily kinases and the oncogenic kinase Met. It exhibits significant antitumor efficacy in Axl-driven and Met-driven tumor models, making it a promising therapeutic candidate for cancer treatment.
The receptor tyrosine kinase Axl plays important roles in promoting cancer progression, metastasis, and drug resistance and has been identified as a promising target for anticancer therapeutics. We used molecular modeling-assisted structural optimization starting with the low micromolar potency compound 9 to discover compound 13c, a highly potent and orally bioavailable Axl inhibitor. Selectivity profiling showed that 13c could inhibit the well-known oncogenic kinase Met with equal potency to its inhibition of Axl superfamily kinases. Compound 13c significantly inhibited cellular Axl and Met signaling, suppressed Axl- and Met-driven cell proliferation, and restrained Gas6/Axl-mediated cancer cell migration or invasion. Furthermore, 13c exhibited significant antitumor efficacy in Axl-driven and Met-driven tumor xenograft models, causing tumor stasis or regression at well-tolerated doses. All these favorable data make 13c a promising therapeutic candidate for cancer treatment.
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