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Basic Information
ID: ALA4823249
Journal: J Med Chem
Title: Discovery of a Pyrimidinedione Derivative as a Potent and Orally Bioavailable Axl Inhibitor.
Authors: Zhang H, Peng X, Dai Y, Shao J, Ji Y, Sun Y, Liu B, Cheng X, Ai J, Duan W.
Abstract: 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.
CiteXplore: 33733758