Abstract LB-319: Development and characterization of ADC999: A novel, potent orally available Wee1 inhibitor with robust antitumor efficacy in vivo

Abstract

Abstract Wee1 is a tyrosine kinase that phosphorylates cyclin-dependent kinase 1 (CDC2) to inactivate 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 has been shown to sensitize p53-deficient tumors to a variety of DNA-damaging anticancer agents. Strong chemosensitization has also been demonstrated in multiple pre-clinical models using targeted agents including CHK1 or PARP inhibitors. These studies combined with recent clinical data demonstrating robust anti-tumor activity in combination with carboplatin or as a single agent in tumors under high replicative stress 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 a novel and highly potent small molecule inhibitor of Wee1 (ADC999) and subsequent analogs. These inhibitors exhibit single digit nM IC50 values against Wee1 and good overall 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, γH2AX and apoptosis induction was also observed in a dose-dependent manner. Further profiling in a panel of cell lines indicated strong anti-proliferative activity both in combination with cytotoxics and in monotherapy. Single agent activity was observed in multiple cancer types, including gynecological, lung and breast. In vivo, oral administration of ADC999 as a single agent led to excellent antitumor activity in a KRAS-mutant non-small cell lung carcinoma xenograft model. Responses ranged from dose-dependent tumor growth inhibition to complete and sustained regressions. ADC999 was well tolerated following a daily dosing regimen and over a prolonged period with no adverse effects observed. Evaluation of ADC999 anti-tumor activity will also be discussed in a panel of genetically-characterized patient-derived xenografts (PDXs) both as monotherapy (mini-trial design) and in combination with PARP inhibitors. In summary, we describe the development and profiling of a novel, highly potent orally available Wee1 inhibitor with robust antitumor efficacy in vivo. This inhibitor and potential back-up compounds will provide new opportunities to fully exploit the therapeutic potential of Wee1 inhibition both as standalone intervention and in combination modalities. Citation Format: Gerald Gavory, Colin O'Dowd, Ewelina Rozycka, Caroline Boyd, Beronia Gorges, Estelle McLean, Julien Daubriac, Shane Rountree, Steven Shepherd, Stephanie Burton, Mary McFarland, Adam Treder, Andy Wilkinson, Frank Burkamp, Tim Harrison. Development and characterization of ADC999: A novel, potent orally available Wee1 inhibitor with robust antitumor efficacy in vivo [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 LB-319. doi:10.1158/1538-7445.AM2017-LB-319