Abstract B17: Development of novel, potent orally available Wee1 inhibitors with robust antitumor efficacy in vivo

Abstract

Abstract Wee1 is a tyrosine kinase that phosphorylates cyclin-dependent kinase 1 (CDC2) to inactive the CDC2/cyclinB complex. Wee1 is therefore a key regulator of the cell cycle, maintaining the G2 checkpoint arrest to allow for pre-mitotic repair upon genomic stress. Unlike normal cells, most p53-deficient tumors lack a functional G1 checkpoint and instead rely on the G2 checkpoint for DNA repair. Abrogation of the G2 checkpoint by a Wee1 inhibitor therefore sensitizes p53-deficient tumors to DNA-damaging anticancer agents and enhances their cytotoxic effect. Strong evidence for chemo-sensitization has been demonstrated in multiple pre-clinical models and also in clinical trials. These clinical observations combined with recent reports demonstrating single agent efficacy make Wee1 a promising target for anticancer therapy. With only one inhibitor (AZD1775) in clinical development and very few reports of compounds at the preclinical stage, the development of alternative Wee1 inhibitors is of significant medical relevance. In this study, we describe the development of novel and highly potent small molecule inhibitors of Wee1 emanating from 2 distinct chemical series (ADC730, ADC999). These inhibitors exhibit single digit nM IC50 values versus the enzyme and good selectivity profiles against the kinome. In cells, target engagement was demonstrated through the inhibition of both CDC2- and CDK2-dependent Wee1 phosphorylation. In line with the mechanism of action, gH2AX and apoptosis induction was also observed in a dose-dependent manner. Further profiling in panels of cell lines indicated strong anti-proliferative activity both in combination with cytotoxics (i.e. gemcitabine) and in monotherapy. Single agent activity was observed in multiple cancer types, including gynecological, lung, colorectal and breast. In vivo, oral administration of ADC730 in combination with gemcitabine resulted in significant dose-dependent growth reduction in a HT29 tumor xenograft model and the combination was synergistic. Dosed orally and as single agents, both ADC730 and ADC999 also demonstrated excellent antitumor activity in the A427 KRAS-mutant lung carcinoma xenograft model. Responses ranged from dose-dependent tumor growth inhibition to complete regressions. ADC730 and ADC999 were well tolerated in these studies with no signs of adverse effects observed. In summary, we describe the development and profiling of novel, highly potent orally available Wee1 inhibitors with robust antitumor efficacy in vivo. These inhibitors will provide new opportunities to fully exploit the therapeutic potential of Wee1 inhibition, either as standalone intervention or in combination modalities. Citation Format: Gerald Gavory, Colin O'Dowd, Ewelina Rozycka, Caroline Boyd, Beronia Gorges, Estelle McLean, Shane Rountree, Steven Sheperd, Stephanie Burton, Mary McFarland, Dominic Janssen, Adam Treder, Andy Wilkinson, Frank Burkamp, Tim Harrison. Development of novel, potent orally available Wee1 inhibitors with robust antitumor efficacy in vivo [abstract]. In: Proceedings of the AACR Special Conference on DNA Repair: Tumor Development and Therapeutic Response; 2016 Nov 2-5; Montreal, QC, Canada. Philadelphia (PA): AACR; Mol Cancer Res 2017;15(4_Suppl):Abstract nr B17.