A dual aurora and lim kinase inhibitor reduces glioblastoma proliferation and invasion

Abstract

High rates of recurrence and treatment resistance in the most common malignant adult brain cancer, glioblastoma (GBM), suggest that monotherapies are not sufficiently effective. Combination therapies are increasingly pursued, but the possibility of adverse drug-drug interactions may preclude clinical implementation. Developing single molecules with multiple targets is a feasible alternative strategy to identify effective and tolerable pharmacotherapies for GBM. Here, we report the development of a novel, first-in-class, dual aurora and lim kinase inhibitor termed F114. Aurora kinases and lim kinases are involved in neoplastic cell division and cell motility, respectively. Due to the importance of these cellular functions, inhibitors of aurora kinases and lim kinases are being pursued separately as anti-cancer therapies. Using in vitro and ex vivo models of GBM, we found that F114 inhibits GBM proliferation and invasion. These results establish F114 as a promising new scaffold for dual aurora/lim kinase inhibitors that may be used in future drug development efforts for GBM, and potentially other cancers.

Keywords: Aurora kinase A (AURKA); Aurora kinase B (AURKB); Aurora kinase C (AURKC); Aurora kinases (AURKs); Fluorescence activated cell sorting (FACS); Glioblastoma (GBM); Induced pluripotent stem cell (iPSC); Lim kinase 1 (LIMK1); Lim kinase 2 (LIMK2); Lim kinases (LIMKs); Temozolomide (TMZ).