Development of potent inhibitors of receptor tyrosine kinases by ligand-based drug design and target-biased phenotypic screening

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Abstract

Pyrazolopyrimidines with potent antiproliferative properties were developed by an adaptive strategy that applies ligand-based design and phenotypic screening iteratively, and is informed by biochemi-cal assays. To drive development towards specific onco-pathways, compounds were tested against cancer cells that overexpress, or not, AXL kinase. Identified phenotypic hits were found to inhibit oncotargets AXL, RET and FLT3. Subsequent optimization generated antiproliferative lead compounds with unique selectivity profiles, including selective AXL inhibitors and a highly-potent inhibitor of FLT3.
Original languageEnglish
Pages (from-to)2104-2110
Number of pages7
JournalJournal of Medicinal Chemistry
Volume61
Issue number5
DOIs
Publication statusPublished - 21 Feb 2018

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