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<p>Protein kinases are central to cell signaling and key drug targets in cancer. To inform potential repurposing of kinase inhibitors, we profiled 86 of the ~100 approved kinase inhibitors against 758 kinases, including 409 wild-type and 349 oncogenic variants using a biochemical kinase assay. Our results increase the number of druggable kinases from 89 to 235, revealing that 94% of mutations and 97% of fusions represented in our samples are inhibited by at least one existing drug. The dataset revealed mutation-specific selectivity, especially in tyrosine kinases FGFR and MET, highlighting gaps and repurposing opportunities. We experimentally validated several actionable findings, including tepotinib to target the IRAK1/4–cholesterol pathway in glioblastoma, brigatinib to target the MARK2/3–Hippo pathway in pancreatic cancer and gilteritinib to overcome <i>MET</i> mutation-driven drug resistance and metastasis. To facilitate exploration of our data, we provide KIRHub, a web-based tool that allows identification of existing inhibitors of wild-type and mutated kinases to guide precision oncology.</p>

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Comprehensive profiling of clinically approved kinase inhibitors reveals mutation-specific inhibitors and opportunities for drug repurposing

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月20日

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  • Mehlam Saifudeen,
  • Songli Zhu,
  • Shuguang Liang,
  • Mia Eason,
  • Alison Goupil,
  • Deanna F. Mische,
  • Christian M. Loch,
  • Haiching Ma,
  • Marina Chan,
  • Taranjit S. Gujral

摘要

Protein kinases are central to cell signaling and key drug targets in cancer. To inform potential repurposing of kinase inhibitors, we profiled 86 of the ~100 approved kinase inhibitors against 758 kinases, including 409 wild-type and 349 oncogenic variants using a biochemical kinase assay. Our results increase the number of druggable kinases from 89 to 235, revealing that 94% of mutations and 97% of fusions represented in our samples are inhibited by at least one existing drug. The dataset revealed mutation-specific selectivity, especially in tyrosine kinases FGFR and MET, highlighting gaps and repurposing opportunities. We experimentally validated several actionable findings, including tepotinib to target the IRAK1/4–cholesterol pathway in glioblastoma, brigatinib to target the MARK2/3–Hippo pathway in pancreatic cancer and gilteritinib to overcome MET mutation-driven drug resistance and metastasis. To facilitate exploration of our data, we provide KIRHub, a web-based tool that allows identification of existing inhibitors of wild-type and mutated kinases to guide precision oncology.