Abstract 3091: Discovery and development of a potent and highly selective WEE1 inhibitor IMP7068

Abstract WEE1 is activated upon DNA damage and regulates the G2/M cell cycle checkpoints. Inhibition of WEE1, in conjunction with genetic alterations and/or a DNA damaging agent, could result in mitotic catastrophe and apoptosis of cancer cells, offering an attractive approach to treat cancer. Small molecule WEE1 inhibitors, such as AZD1775, showed good clinical POC (proof of concept) data in several tumors including ovarian, colon, and uterine carcinoma. We have identified a novel, potent, and highly selective WEE1 inhibitor IMP7068. Herein we will present its discovery and IND enabling in vitro and in vivo studies. IMP7068 exhibits superior WEE1/PLK1 selectivity (>435 fold) compared to AZD1775. IMP7068 also shows potent cytotoxicity against a wide range of cancer cell lines. In addition, IMP7068 has desirable PK profiles with long half-life and high exposure in preclinical species. Anti-tumor efficacy of IMP7068 has been demonstrated in mice CDX models of colorectal LoVo, non-small cell lung cancer NCI-H1299 and a PDX model of uterine UT5318 with good dose-response tumor inhibition and tolerability. IMP7068 is currently in a phase I study to evaluate its safety, tolerability, pharmacokinetics, and anti-tumor activity in patients with advanced solid tumors (ClinicalTrials.gov Identifier: NCT04768868). Citation Format: Sui Xiong Cai, Ning Ma, Xiaozhu Wang, Yangzhen Jiang, Hongxia Zhang, Mingchuan Guo, Ruiyu Zhou, Ye Edward Tian. Discovery and development of a potent and highly selective WEE1 inhibitor IMP7068 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3091.