Development of Potent Inhibitors of Receptor Tyrosine Kinases by Ligand-Based Drug Design and Target-Biased Phenotypic Screening

作者：Myers Samuel H; Temps Carolin; Houston Douglas R; Brunton Valerie G; Unciti Broceta Asier^*

来源：Journal of Medicinal Chemistry, 2018, 61(5): 2104-2110.

DOI：10.1021/acs.jmedchem.7b01605

Pyrazolopyrimidines with potent antiproliferative properties were developed by an adaptive strategy that applies ligand-based design and phenotypic screening iteratively and is informed by biochemical assays. To drive development toward specific oncopathways, 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.

• 出版日期2018-3-8