Abstract 292: Synthesis and characterization of the novel benzylindazole-based BUB1 kinase inhibitor BAY 1816032 with potent anti-tumor activity

Abstract

Abstract BUB1 (budding uninhibited by benzimidazoles 1) is a serine/threonine protein kinase. The protein is bound to kinetochores and plays a key role in the establishment of the mitotic spindle checkpoint and chromosome congression prior to anaphase. Inhibition of BUB1 kinase represents a novel approach for cancer treatment: whereas cell cycle arrest is the predominant mode of action of a number of antimitotic cancer drugs (e.g. taxanes and vinca alkaloids), BUB1 inhibition results in aneuploidy and cell death by driving cells through mitosis irrespective of misattached chromosomes. Here, we disclose for the first time the structure and functional characterization of a novel, first-in-class Bub1 kinase inhibitor. Medicinal chemistry efforts resulted in BAY 1816032 featuring high potency, long target residence time and good oral bioavailability. BAY 1816032 is highly selective for BUB1 displaying single digit nanomolar biochemical potency and double-digit nanomolar cellular potency (H2A induced HeLa-cells). Synergistic effects can be observed when BUB1 inhibitor BAY 1816032 is combined with low doses of paclitaxel affecting chromosome segregation and cell proliferation. X-ray data of benzylindoles allowed a better understanding of the binding mode. Further data on structure-activity relationships including pharmacokinetic characterization, drug metabolism and the synthesis of BAY 1816032 and analogues will be presented. These results validate the innovative concept of interference with mitotic checkpoints and justify clinical proof of concept studies evaluating BUB1 inhibitor BAY 1816032 in combination with taxanes in order to enhance their efficacy and to potentially overcome resistance. Citation Format: Marion Hitchcock, Anne Mengel, Carl Nising. Synthesis and characterization of the novel benzylindazole-based BUB1 kinase inhibitor BAY 1816032 with potent anti-tumor activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 292. doi:10.1158/1538-7445.AM2017-292