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

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 inhib...
Source: Molecular Cancer Research - Category: Cancer & Oncology Authors: Tags: Therapies Targeting Checkpoints and Mismatch Repair: Poster Presentations - Proffered Abstracts Source Type: research