Abstract A152: Emerging indications for kinase-targeted therapies: screening for new targets

Abstract Protein kinases play key roles in normal physiologic functions. Aberration of individual protein kinases and the pathways that these enzymes govern are centrally involved in the pathogenesis of a number of diseases including cancer, neurologic disorders, metabolic diseases, and autoimmune conditions. Targeting these enzymes using small-molecule approaches has been proven to be highly relevant in terms of treating cancer and, more recently, autoimmune conditions like rheumatoid arthritis. Evaluating the specificities of these compounds across the kinome and relating these effects with clinical manifestations may provide important insights into how these compounds can be used to treat other diseases. In this study, we evaluated the specificity of four compounds–saracatinib, vandetanib, crizotinib, and cabozantinib–across a panel of 48 kinases representing 7 major groups and other kinases. They were assessed at 1 and 10 µM using the “gold standard” radiometric assay. A 50% reduction in kinase activity at the single point concentration at 1 μM was deemed to be of relevance in this study as that would signify an IC50 of less than 1 µM. The study demonstrated that all four compounds inhibited greater than 30% of the kinases within this 48-kinase panel, albeit different kinase targets. Interestingly, none of the selected kinases within AGC, CAMK, and CGMC subgroups was inhibited more than 50% at 1 μM. Furthermore, all 4 inhibitors exhibited greatest potency against their intended kinase targets, mainly receptor and cytoplasmic tyrosine kinases, RTKs, and CTKs, respectively. Specifically, saracatanib inhibited PDGFR, KIT, EGFR, and BTK; vandetanib inhibited FGFR2 and KDR, an RTK that interacts with the ligand VEGF; crizotinib inhibited insulin receptor (InsR); and cabozantinb had effect on DDR2, FLT1, FLT3, KDR, MET, and TRKA. In conclusion, we have demonstrated the power of using unbiased protein kinase panels to uncover novel biochemical interactions with potential therapeutic values. Of the four inhibitors tested above, we have found several new targets for each, including an interaction between crizotinib and insulin receptor, an RTK involved in metabolic homeostasis. This opens up possible implications for crizotinib in regulating metabolic homeostasis. Citation Format: Rick Li, Shenshen Lai, Allan Mah, Hong Zhang, Jun Yan, Anthony Marotta, Zaihui Zhang. Emerging indications for kinase-targeted therapies: screening for new targets [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A152.

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