Divergent polypharmacology-driven cellular activity of structurally similar multi-kinase inhibitors through cumulative differential effects on individual targets: IMAC Phosphoproteomics

Despite recent successes of precision and immunotherapies there is a persisting need for novel targeted or multi-targeted approaches in complex diseases. Through a systems pharmacology approach including phenotypic screening, chemical and phosphoproteomics and RNA-Seq, we elucidated the targets and mechanisms underlying the differential anticancer activity of two structurally related multi-kinase inhibitors, foretinib and cabozantinib, in lung cancer cells. Biochemical and cellular target validation using probe molecules and RNA interference revealed a polypharmacology mechanism involving MEK1/2, FER and AURKB, which were each more potently inhibited by foretinib than cabozantinib. Based on this, we developed a synergistic combination of foretinib with barasertib, a more potent AURKB inhibitor, for MYC-amplified small cell lung cancer. This systems pharmacology approach showed that small structural changes of drugs can cumulatively, through multiple targets, result in pronounced anticancer activity differences and that detailed mechanistic understanding of polypharmacology can enable repurposing opportunities for cancers with unmet medical need.

尽管精准治疗与免疫治疗近年来已取得诸多突破，但针对复杂疾病，仍亟需开发新型靶向或多靶点治疗策略。本研究通过涵盖表型筛选、化学蛋白质组学、磷酸化蛋白质组学及RNA测序（RNA-Seq）的系统药理学（systems pharmacology）策略，阐明了两种结构相似的多激酶抑制剂——福替尼（foretinib）与卡博替尼（cabozantinib）在肺癌细胞中展现差异化抗癌活性的靶点与作用机制。借助探针分子与RNA干扰开展的生化及细胞水平靶点验证实验，本研究揭示了一种涉及MEK1/2、FER及AURKB的多药理学机制，且福替尼对上述三者的抑制活性均强于卡博替尼。基于上述发现，本研究针对MYC扩增型小细胞肺癌，开发了福替尼与活性更强的AURKB抑制剂巴拉塞替尼（barasertib）的协同联合疗法。本研究所采用的系统药理学策略表明，药物微小的结构变化可通过多靶点的累积效应，带来显著的抗癌活性差异；而对多药理学的深入机制解析，可为存在未被满足医疗需求的癌症类型提供药物重定位的机遇。