berzosertib (M6620)

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.

PMDOs can be completely eradicated if MMC treatment is followed by inhibition of ATR or other DDR kinases. DDR inhibitors may therefore have value in the adjuvant treatment of peritoneal metastases following CRS-HIPEC.

Molecular docking identified YM-201636 and VE-822 (Berzosertib) as potential drugs targeting CDKN2A, both showing promise for LUAD treatment in vivo. PASEs constitute a comprehensive biomarker for predicting prognosis and monitoring the TIME in LUAD patients. Specifically, CDKN2A stands out as a potential prognostic biomarker and drug target for LUAD.

This novel combination of ATR inhibitor berzosertib with irinotecan did not lead to objective responses in patients with TP53-mutated, advanced gastroesophageal adenocarcinoma. The combination regimen was well tolerated without unexpected adverse events. This trial was registered with ClinicalTrials.gov (NCT03641313).

Berzosertib 270 mg/m2 and irinotecan 180 mg/m2 was the RP2D. The combination is associated with manageable side effects and promising disease activity in ATM mutant solid tumors.

We used AZD0156, an ATM inhibitor, and VE-822, an ATR inhibitor, in combination with normo-fractionated RT to treat two HPV-positive and two HPV-negative HNSCC cell lines. In co-culture with NK cells, an upregulation of activation markers on NK cells was observed, particularly after contact with RT + ATMi-treated HPV-negative HNSCC cells. We conclude that ATM inhibitor-related induction of senescence in HNSCC cells shapes the tumor micro-environment in way that NK cell phenotype is changed.

The present study developed a PRS using 101 machine learning combination algorithms, which could aid in risk stratification and prognosis for LUAD patients. The candidate drugs and target may provide new insights in the treatment of high PRS group patients.

Here, we demonstrate a remarkable potency of the PARPi talazoparib in HRD PDAC. Substituting olaparib, currently the only approved inhibitor in PDAC, with talazoparib in our PAD regimen enhanced its efficacy while maintaining comparable tolerability in vivo. Importantly, we show that PAD is an effective therapeutic regimen that can be extended to the most prevalent HR-defective genotypes in PDAC including ATM, BRCA1, BRCA2 and PALB2 in a preclinical setting. Collectively, these data provide a strong rationale to implement the refined regimen, talazoparib-based PAD, as a therapeutic concept tailored for HRD PDAC patients.

P1, N=42, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Nov 2025 --> Apr 2026 | Trial primary completion date: Nov 2025 --> Apr 2026