berzosertib (M6620)

Natural killer cells showed only a limited contribution to the killing of HNSCC cells pretreated with RT or RT + DDRi. However, a subset of patients with head and neck tumors-such as those represented by the HSC4 model-might still benefit from combining RT with ATMi rather than ATRi to enhance NK cell-mediated tumor killing.

P1/2, N=12, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: May 2026 --> Mar 2027

Additionally, drug sensitivity prediction analysis demonstrated that MSTN expression was significantly associated with sensitivity to paclitaxel and VE-822, while TCF12 expression showed potential associations with sensitivity to cytarabine, olaparib, Wee1 inhibitor, paclitaxel, and VE-822. Immunofluorescence confirmed upregulated expression of MSTN and TCF12 in glioma tissues and their co-localization with macrophages. In conclusion, this study identified TAFCs as the central cells in the glioma microenvironment, with their signature genes MSTN and TCF12 representing candidate immunometabolic signatures associated with macrophage-mediated immunosuppression and metabolic reprogramming in glioma, suggesting their potential as biomarkers for patient stratification and as targets for immunometabolic therapies.

P1/2, N=12, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Apr 2025 --> May 2026

P1/2, N=120, Recruiting, National Cancer Institute (NCI) | Trial completion date: Mar 2027 --> Mar 2029 | Trial primary completion date: Mar 2026 --> Mar 2028

P1, N=66, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Mar 2026 --> Mar 2027

P1/2, N=37, Active, not recruiting, National Cancer Institute (NCI) | Recruiting --> Active, not recruiting | N=120 --> 37 | Trial primary completion date: Aug 2026 --> Dec 2025

P2, N=17, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Jan 2026 --> Jan 2027

We provide a detailed analysis of the structure-activity relationships (SAR) of leading clinical candidates, including berzosertib, ceralasertib, and elimusertib, focusing on strategic chemical modifications such as scaffold hopping and sulfoximine substitution to optimize selectivity and druggability. Critical challenges, specifically dose-limiting hematological toxicities and acquired resistance, are analyzed alongside the search for robust predictive biomarkers. By synthesizing current pharmacological and clinical data, this work outlines the trajectory for next-generation ATR-targeted precision medicine.

Over the last decade, intensive medicinal chemistry efforts have generated a broad pipeline of ATR inhibitors, including ceralasertib, elimusertib, camonsertib, berzosertib, ART0380, and gartisertib, many of which are in Phase I/II clinical trials. Incorporating these strategies into adaptive platform trials with pharmacodynamic markers and patient-centered outcomes will speed up translation. Overall, ATR inhibitors highlight progress in DNA damage response therapies, from understanding mechanisms to biomarker-driven clinical use, with the potential to revolutionize treatment across various cancers.

P1, N=42, Active, not recruiting, National Cancer Institute (NCI) | Trial primary completion date: Apr 2026 --> Feb 2027 | Trial completion date: Apr 2026 --> Feb 2027

We provide novel data on the efficacy of putative and established therapies in patient-derived GEP-NEN primary cultures. Our standardized platform for personalized drug screening and risk assessment in GEP-NEN primary cultures enables prediction of individual tumor treatment response in this orphan disease.