Judith Guenther

Novel Class of Potent and Cellularly Active Inhibitors Devalidates MTH1 as Broad-Spectrum Cancer Target

MTH1 is a hydrolase responsible for sanitization of oxidized purine nucleoside triphosphates to prevent their incorporation into replicating DNA. Early tool compounds published in the literature inhibited the enzymatic activity of MTH1 and subsequently induced cancer cell death; however recent studies have questioned the reported link between these two events. Therefore, it is important to validate MTH1 as a cancer dependency with high quality chemical probes. Here, we present BAY-707, a substrate-competitive, highly potent and selective inhibitor of MTH1, chemically distinct compared to those previously published. Despite superior cellular target engagement and pharmacokinetic properties, inhibition of MTH1 with BAY-707 resulted in a clear lack of in vitro or in vivo anticancer efficacy either in mono- or in combination therapies. Therefore, we conclude that MTH1 is dispensable for cancer cell survival.

Abstract 3248: Identification and optimization of a highly active, cross reactive Complex-1 inhibitor

Mitochondria are key regulators of both energy supply and apoptotic cell death. The mitochondrial electron transport chain (ETC) consists of four enzyme complexes that transfer electrons from NADH to oxygen. During electron transfer, the ETC pumps protons into the inter-membrane space, generating a gradient across the inner mitochondrial membrane that is used by Complex V to drive ATP synthesis. Recent publications have shown that tumor cells harboring specific mutations (LKB1, mIDH and others) are more sensitive to Complex I inhibition, potentially providing an opportunity for selectively targeting tumor cells. Based on a high throughput screen (HTS), we identified new, albeit moderately active, lead structures with cross reactivity between mouse and human Complex 1. SAR elaboration of the lead structure allowed for optimization of the potency, although compounds still suffered from low metabolic stability. Further improvement of the in vitro and in vivo PK properties finally permitted in vivo animal studies. Herein, we report for the first time the preclinical profile and structure of a highly active, optimized, human/mouse cross-reactive Complex I inhibitor that allowed for the further investigation into the therapeutic potential of Complex I inhibition in cancer. Citation Format: Jeffrey Mowat, Sven Christian, Carolyn Sperl, Alexander Ehrmann, Stephan Menz, Judith Guenther, Roman Hillig, Marcus Bauser, Andrea Haegebarth, Wolfgang Schwede. Identification and optimization of a highly active, cross reactive Complex-1 inhibitor [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 3248. doi:10.1158/1538-7445.AM2017-3248