Abstract 6177: ATRN-119 and ATRN-W1051: Novel and potentially well tolerated ATR and WEE1 inhibitors for targeted cancer treatment

Abstract

Abstract Previous studies have demonstrated the promise of ATR and WEE1 inhibitors (ATRi and WEE1i) as cancer treatments. Inhibition of these DNA replication checkpoint kinases disrupts normal DNA synthesis and causes replication fork collapse, and these effects are accentuated by numerous cancer-associated mutations. However, a key limitation to this approach in clinical trials has been the occurrence of adverse hematological effects, including anemia, neutropenia, and thrombocytopenia. Herein, we describe two novel inhibitors, ATRN-119 (ATRi) and ATRN-W1051 (WEE1i), that exhibit increased target selectivity that potentially decreases these dose-limiting toxicities. ATRN-119, the first macrocyclic ATRi to enter clinical trials, is highly specific for inhibition of ATR relative to other phosphatidylinositol kinase-related kinases (PIKKs), such as ATM, DNA-PK, and MTOR. This specificity correlates with increased tolerability, which permits continuous dosing in animal models. Importantly, dose scheduling of ATRN-119 that suppresses tumor growth in xenograft mouse models of colon, pancreatic, and prostate cancers causes no appreciable loss of body weight or hematologic toxicity (anemia, neutropenia or thrombocytopenia). Daily dosing is also tolerated in combination with PARP inhibition, which causes significant tumor reduction in a BRCA2-defient PDX model of high-grade serous ovarian cancer. These findings have led a biomarker-driven Phase I clinical trial of ATRN-119 with daily dosing for ovarian and other cancers (Simpkins, PI). To potentially reduce the toxicity of WEE1i, a new potent and selective WEE1 inhibitor, ATRN-W1051, was developed. In vitro, ATRN-W1051 inhibits WEE1 with an IC50 of 2.2 nM and limits the proliferation of ovarian cancer cell lines in the 100 nM to 200 nM range. Importantly, ATRN-W1051 exhibits low off-target inhibition of the PLK family of kinases (PLK1, PLK2 and PLK3), which are substantially inhibited by the leading WEE1i in the clinic (AZD1775 and ZN-c3)1. In addition, ATRN-W1051 also has potentially favorable pharmacokinetic properties that permits 3-8 times lower dosing than AZD1775 or ZN-c3 to achieve similar exposure (AUC0-24) levels2. Notably, daily oral dosing of ATRN-W1051 is well tolerated in mice and suppresses the growth of CCNE1-amplified HGSOC xenografted tumors. These preclinical data suggest that ATRN-W1051 may be a potential therapeutic candidate for CCNE1-overexpressing HGSOC. Together, ATRN-119 and ATRN-W1051 provide promising alternative DNA replication checkpoint inhibitors for the treatment of a variety of cancers. Citation Format: Joseph Vacca, Stephen Rocca, Justin Frye, Steven J. Schnell, Molly Hansbarger, Gregory Korbel, Fiona Simpkins, Eric J. Brown, Oren Gilad. ATRN-119 and ATRN-W1051: Novel and potentially well tolerated ATR and WEE1 inhibitors for targeted cancer treatment [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 6177.