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Nucleic Acids as Therapeutic Targets and Agents
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Berzosertib (VX-970) was the first potent (i.e., Ki = <0.3 nM) and highly selective ATR inhibitor to enter clinical development. In preclinical studies it markedly increased the cytotoxic activity of multiple DNA-damaging agents across many different cancer cell lines, while having good tolerability in normal cells without activating compensatory ATM-mediated repair pathways. Interestingly, defects in the ATM pathway, for example, as a result of mutations in the TP53 gene that encodes p53 (a principle substrate for ATM), were found to be predictive of sensitivity in tumor cell lines. In addition, VX-970 had marked cytotoxic activity when combined with PARP inhibitors, and in mouse xenograft models it strongly potentiated the activity of DNA-damaging agents including cisplatin, carboplatin, irinotecan, and gemcitabine. Overall, the data suggested that the cancer cell specificity for this combination was associated, at least in part, with dysregulated ATM-p53 pathway signaling. The single-agent activity of VX-970 in some cancer cell lines appeared to require the simultaneous presence of defects in alternative DNA-repair pathways and high background replication stress levels.
Inhibitors of phosphoinositide 3-kinase (PI3K) and phosphoinositide 3-kinase-related protein kinase family (PIKK)
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2023
Xueqin Huang, Li You, Eugenie Nepovimova, Miroslav Psotka, David Malinak, Marian Valko, Ladislav Sivak, Jan Korabecny, Zbynek Heger, Vojtech Adam, Qinghua Wu, Kamil Kuca
Berzosertib is a powerful ATR inhibitor administered intravenously and is currently being evaluated by Merck. To improve the targeted therapy of selective inhibitors, it is possible to target defective pathways in cancer cells, use synthetic lethal interactions to kill cancer cells or rely on synergy with other drugs to enhance anticancer effects185. In the phase I study, the berzosertib plus gemcitabine group had a partial response of 8.3% and a stable disease of 60.4%186. In the berzosertib plus gemcitabine plus cisplatin group, partial response (PR) was 14% and stable disease was 57%. Additionally, berzosertib was well tolerated only in combination with cisplatin-free gemcitabine, so the suggested phase II dose (RP2D) for this combination was established186. Following that, a phase II trial of berzosertib plus gemcitabine in high-grade serous ovarian cancer was conducted. Berzosertib combined with gemcitabine significantly prolonged PFS compared to gemcitabine alone (22.9 weeks vs. 14.7 weeks), and the combination therapy reduced the proportion of patients with severe adverse reactions (26% vs. 28%)187. Berzosertib has good BBB penetration in preclinical studies of GBM. Studies have shown that berzosertib exhibits a radiosensitizing effect in preclinical NSCLC brain metastases models, so a clinical trial of berzosertib combined with whole brain irradiation for patients with NSCLC brain metastases is currently underway188.
Defining and targeting wild-type BRCA high-grade serous ovarian cancer: DNA repair and cell cycle checkpoints
Published in Expert Opinion on Investigational Drugs, 2019
S. Percy Ivy, Charles A. Kunos, Fernanda I. Arnaldez, Elise C. Kohn
Berzosertib (VX970 or M6620) is a potent intravenous inhibitor of ATR. Berzosertib monotherapy is inactive; combinational approaches are under evaluation for HGSOC. An ongoing randomized phase II study testing gemcitabine (1,000 mg m−2 day 1 and 8 per 21-day cycle) ± berzosertib (210 mg m−2 on days 2 and 9) for women with refractory or recurrent metastatic platinum-resistant ovarian cancer (NCT02595892). Women with platinum-sensitive HGSOC, including those with gBRCA disease, are being recruited to a second seamless phase I/II study (NCT02627443) evaluating gemcitabine (480–800 mg m−2 on day 1, 8 repeated every 21 days), carboplatin (AUC 4 on day 1), and berzosertib (90–120 mg m−2 on days 2, 9).
Discovery of small-molecule ATR inhibitors for potential cancer treatment: a patent review from 2014 to present
Published in Expert Opinion on Therapeutic Patents, 2022
Suwen Hu, Zi Hui, Jilong Duan, Carmen Garrido, Tian Xie, Xiang-Yang Ye
Berzosertib (M6620, VX-970) is the first ATR inhibitor entering clinical trials. It was discovered by Vertex Pharmaceuticals Incorporated through the optimization of the lead VE-821 [49]. It is a potent and selective ATR inhibitor with greater than 1000 times selectivity over DNA-PK (ATR enzyme IC50 = 0.17 nM; DNA-PK IC50 > 4000 nM) [51]. Currently, there are at least 21 registered clinical trials (Table 7) in Phase I/II stages in which berzosertib is used as monotherapy or in combination with DNA damaging chemotherapies and radiation therapy [52]. In 2018, Pommier et al. released the Phase I study of berzosertib in combination with topotecan in 3-week cycles using 3 + 3 dose escalation. This appears to be the first report of an ATR inhibitor–chemotherapy combination. Such combination seems particularly active in platinum-refractory small-cell lung cancer, which tends not to respond to topotecan alone [52]. The phase I trial using the combination of berzosertib with carboplatin in patients with advanced solid tumors has also been completed [53]. The results suggest berzosertib was well tolerated, with target engagement and preliminary antitumor responses observed. Similarly, berzosertib plus cisplatin or berzosertib plus gemcitabine trials are found to be well tolerated and show preliminary clinical activity in patients with advanced solid tumors, warranting further evaluation in a phase II setting [54,55]. Kimple et al. reported that the combination of M6620 and radiation resulted in improved overall survival in mice bearing non-small cell lung cancer (NSCLC) brain metastases [56]. The results support supporting the ongoing clinical trial (NCT02589522) using M6620 in combination with whole brain irradiation in patients with NSCLC brain metastases. However, in most recent release phase II trial reported by Pal et al, the addition of berzosertib to cisplatin with gemcitabine did not prolong progression-free survival relative to cisplatin with gemcitabine alone in patients with metastatic urothelial cancer, and a trend toward inferior survival was observed with this combination. Berzosertib plus cisplatin with gemcitabine was associated with significantly higher hematologic toxicities despite attenuated dosing of cisplatin with gemcitabine [57].