Abstract Previous studies have demonstrated WEE1i and ATR inhibitors (ATRi and WEE1i) to be promising cancer therapeutics through synthetic lethality with various cancer associated mutations. However, a key limitation to the use of these inhibitors as cancer therapies in prior clinical trials has been the occurrence of adverse hematological effects, including anemia and thrombocytopenia. Herein, we describe two novel inhibitors, ATRN-1051 (WEE1i) and ATRN-119 (ATRi) that are potentially both effective in tumor suppression in animal models and well tolerated. ATRN-1051 was developed to be both a potent WEE1i and selective for WEE1 over other kinases (PLK1, PLK2 and PLK3). ATRN-1051 has an IC50 of 2.2 nM for WEE1 and limits the proliferation of various cancer cell lines in culture in the 100 nM to 200 nM range. Notably, ATRN-1051 is particularly effective in suppressing the growth of Cyclin E overexpressing cells lines, pinpointing Cyclin E as a potential biomarker for ATRN-1051. In addition, ATRN-1051 has potentially favorable pharmacokinetic properties that permits 3-8 times lower dosing than other clinical WEE1 inhibitors to achieve similar exposure (AUC, 0-24) levels (1). Consistent with the increase selectivity of ATRN-1051 fostering increased tolerability, dose-range finding studies indicate that doses potentially expected to cause significant tumor suppression are hematological well tolerated in mice, with red blood cell and platelet counts remaining in a non-pathogenic range. Importantly, daily oral dosing of ATRN-1051 suppresses the growth of CCNE1-amplified high-grade serous ovarian xenografted tumors over the course of 28 days, providing further evidence of the role of CCNE1-overexpression as a biomarker for ATRN-1051 treatment. Based on these data, ATRN-1051 has entered and is now progressing through IND-enabling studies. As a distinct upstream DNA replication checkpoint inhibitor, ATRN-119 is a macrocyclic ATRi that is highly specific for inhibition of ATR over other phosphatidylinositol kinase-related kinases (PIKKs), such as ATM, DNA-PK, and MTOR, implying the potential for increased tolerability. Supporting this implication, daily dosing of ATRN-119 suppresses tumor growth in xenograft mouse models of colon, pancreatic, and prostate cancers and causes no appreciable loss of body weight or hematologic toxicity. Daily dosing of ATRN-119 in combination with PARP inhibition causes significant tumor reduction in a BRCA2-deficient PDX model of high-grade serous ovarian cancer, again with no appreciable loss of body weight. These findings have led to a biomarker-driven Phase 1/2a clinical trial of ATRN-119 with daily dosing (Simpkins, PI). Together, these findings underscore the promise of ATRN-1051 and ATRN-119 as DNA replication checkpoint inhibitors for the treatment of a variety of cancers. (1) Data from study in A-427 NSCLC xenograft model as reported in Zentalis Corporate Overview, March 2022 Citation Format: Joseph Vacca, Stephen Rocca, Molly Hansbarger, Sonia Ritzmann, Justin Frye, Fiona Simpkins, Eric J. Brown, Oren Gilad. The DNA replication checkpoint inhibitors, ATRN-1051 (WEE1i) and ATRN-119 (ATRi), are potentially well tolerated and effective cancer treatments [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C147.
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Apr 16, 2024
Yesim Yekta Yuruk + 1
Open Access