Identification And Preclinical Characterisation Of Ver-250840, A Potent, Selective Chk1 Inhibitor With In Vivo Oral Single-Agent Antitumor Activity

On sustaining damage to their DNA, cells employ a sophisticated mechanism of detection and repair, termed the DNA damage response (DDR). As a critical component of the DDR and G2/M checkpoint, Chk1 kinase represents an attractive target for cancer therapy. We have utilized a structure-based drug design approach to identify and develop VER-250840, a novel, orally active inhibitor of the checkpoint kinase, Chk1. VER-250840 exhibited sub-nM potency against Chk1 kinase with exquisite selectivity over an extensive and diverse panel of kinases. In vitro, VER-250840 inhibited Chk1 autophosphorylation with an IC 50 of 1.0 nM and increased the number of S-phase tumor cells staining positive for pan-nuclear γH2AX with an EC 50 of 7 - 27 nM. Accumulated genomic DNA damage by Chk1 inhibition led to irreversible cell cycle arrest, inhibition of tumor cell proliferation, increased replication stress, and cell death in both 2D culture and multicellular tumor spheroids. In an in vivo A2058 tumor xenograft PD study, VER-250840 demonstrated rapid and sustained inhibition of Chk1 auto-phosphorylation within 30 minutes of oral administration. Doses of 10 mg/kg and higher PO resulted in greater than 90% inhibition of tumor pChk1 (S296) over 24 hours. In SKOV3 in vivo models, VER-250840 inhibited Chk1 auto-phosphorylation, modulated other biomarkers of replication stress and DNA damage, and exhibited moderate antitumor activity with minimal toxicity when administered orally on a 21-day once-daily schedule. Work is ongoing to further optimize in vivo efficacy. In conclusion, VER-250840 demonstrates potent and selective activity as a monotherapy both in vitro and in vivo. From these findings, further evaluation and optimization of this novel kinase inhibitor is justly merited. Citation Format: Joanne Wayne, Stephen Stokes, Nicolas Foloppe, Helen Browne, Teresa Brooks, Karen Benwell, Lisa Baker, Zoe Daniels, Andrea Fiumana, Christopher Graham, Alba Macias, Daniel Maddox, Sean McKenna, Christopher Northfield, Stuart Ray, Heather Simmonite, Emma Stefaniak, Paul Webb, Mike Wood, Andrew Massey. Identification and preclinical characterisation of VER-250840, a potent, selective Chk1 inhibitor with in vivo oral single-agent antitumor activity [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B163.