vx-970 and Neoplasms

Chemoresistance, radioresistance, and the challenge of achieving complete resection are major driving forces in the search for more robust and targeted anticancer therapies. Targeting the DNA damage response has recently attracted research interest, as these processes are enhanced in tumour cells. The major replication stress responder is ATM and Rad3-related (ATR) kinase, which is attracting attention worldwide with four drug candidates currently in phase I/II clinical trials. This review addresses a potent and selective small-molecule ATR inhibitor, which is known as VX-970 (also known as berzosertib or M6620), and summarizes the existing preclinical data to provide deep insight regarding its real potential. We also outline the transition from preclinical to clinical studies, as well as its relationships with other clinical candidates (AZD6738, VX-803 [M4344], and BAY1895344). The results suggest that VX-970 is indeed a promising anticancer drug that can be used both as monotherapy and in combination with either chemotherapy or radiotherapy strategies. Based on patient anamnesis and biomarker identification, VX-970 could become a valuable tool for oncologists in the fight against cancer.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Ataxia Telangiectasia Mutated Proteins; Drug Discovery; Drug Synergism; Humans; Isoxazoles; Molecular Targeted Therapy; Neoplasms; Protein Kinase Inhibitors; Pyrazines; Signal Transduction; Sulfones; Treatment Outcome

The chemical treatment of cancer started with the realization that DNA damaging agents such as mustard gas present notable antitumoural properties. Consequently, early drug development focused on genotoxic chemicals, some of which are still widely used in the clinic. However, the efficacy of such therapies is often limited by the side effects of these drugs on healthy cells. A refinement to this approach is to use compounds that can exploit the presence of DNA damage in cancer cells. Given that replication stress (RS) is a major source of genomic instability in cancer, targeting the RS-response kinase ataxia telangiectasia and Rad3-related protein (ATR) has emerged as a promising alternative. With ATR inhibitors now entering clinical trials, we here revisit the biology behind this strategy and discuss potential biomarkers that could be used for a better selection of patients who respond to therapy.

Topics: Ataxia Telangiectasia Mutated Proteins; DNA Damage; Drug Development; Genomic Instability; Humans; Indoles; Isoxazoles; Molecular Targeted Therapy; Morpholines; Neoplasms; Nitroso Compounds; Oxazines; Protein Kinase Inhibitors; Pyrazines; Pyrimidines; Quinolines; Sulfonamides; Sulfoxides

In this article, we review the ATR inhibitor field from initial pharmacological tools to first-generation clinical candidates with the potential to bring benefit to cancer patients. ATR is a critical part of the cell DNA-damage response. Over the past decade or more, compounds with weak ATR potency and low specificity have been used as tools in early studies to elucidate ATR pharmacology. More recently highly potent, selective and in vivo active ATR inhibitors have been developed enabling detailed preclinical in vitro and in vivo target assessment to be made. The published studies reveal the potential of ATR inhibitors for use as monotherapy or in combination with DNA-damaging agents. To date, VX-970 and AZD6738, have entered clinical assessment.

Topics: Antineoplastic Agents; Ataxia Telangiectasia Mutated Proteins; DNA Damage; Humans; Isoxazoles; Molecular Conformation; Neoplasms; Pyrazines

Berzosertib (formerly M6620) is the first-in-class inhibitor of ataxia-telangiectasia and Rad3-related protein, a key component of the DNA damage response, and being developed in combination with chemotherapy for the treatment of patients with advanced cancers. The objectives of this analysis were to characterize the pharmacokinetics (PK) of berzosertib across multiple studies and parts, estimate inter-individual variability, and identify covariates that could explain such variability.. A population PK analysis was performed using the combined dataset from two phase I clinical studies (NCT02157792, EudraCT 2013-005100-34) in patients with advanced cancers receiving an intravenous infusion of berzosertib alone or in combination with chemotherapy. The analysis included data from 240 patients across 11 dose levels (18-480 mg/m. PK data were best described by a two-compartment linear model. For a typical patient, the estimated clearance (CL) and intercompartmental CL were 65 L/h and 295 L/h, respectively, with central and peripheral volumes estimated to be 118 L and 1030 L, respectively. Several intrinsic factors were found to influence berzosertib PK, but none were considered clinically meaningful due to a very limited effect. Model simulations indicated that concentrations of berzosertib exceeded p-Chk1 (proximal pharmacodynamic biomarker) IC. There was no evidence of a clinically significant PK interaction between berzosertib and evaluated chemo-combinations. The covariate analysis did not highlight any need for dosing adjustments in the population studied to date.. NCT02157792, EudraCT 2013-005100-34.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Ataxia Telangiectasia Mutated Proteins; Dose-Response Relationship, Drug; Female; Humans; Infusions, Intravenous; Inhibitory Concentration 50; Isoxazoles; Male; Middle Aged; Models, Biological; Neoplasms; Protein Kinase Inhibitors; Pyrazines

A phase I trial of the novel combination of the ataxia telangiectasia and Rad3-related inhibitor berzosertib plus the antibody-drug conjugate sacituzumab govitecan in patients with heavily pretreatment tumors demonstrated some antitumor activity and no dose-limiting toxicities. This represents a new treatment paradigm that will be further explored in a phase II setting. See related article by Abel et al., p. 3603.

Topics: Camptothecin; Humans; Immunoconjugates; Neoplasms