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

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.