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.

中文翻译：

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通过基于配体的药物设计和靶点偏爱的表型筛选开发受体酪氨酸激酶的强效抑制剂。

具有有效抗增殖特性的吡唑并嘧啶是通过一种适应性策略开发的，该策略可反复应用基于配体的设计和表型筛选，并通过生化分析获得信息。为了推动向特定途径的发展，已经针对过表达或未过表达AXL激酶的癌细胞对化合物进行了测试。发现已确定的表型命中可以抑制癌标靶AXL，RET和FLT3。随后的优化产生了具有独特选择性的抗增殖先导化合物，包括选择性AXL抑制剂和高效FLT3抑制剂。