Rational Design of 5-(4-(Isopropylsulfonyl)phenyl)-3-(3-(4-((methylamino)methyl)phenyl)isoxazol-5-yl)pyrazin-2-amine (VX-970, M6620): Optimization of Intra- and Intermolecular Polar Interactions of a New Ataxia Telangiectasia Mutated and Rad3-Related (ATR) Kinase Inhibitor

The DNA damage response (DDR) secures the integrity of the genome of eukaryotic cells. DDR deficiencies can promote tumorigenesis but concurrently may increase dependence on alternative repair pathways. The ataxia telangiectasia and Rad3-related (ATR) kinase plays a central role in the DDR by activating essential signaling pathways of DNA damage repair. Here, we studied the effect of the novel selective ATR kinase inhibitor BAY 1895344 on tumor cell growth and viability. Potent antiproliferative activity was demonstrated in a broad spectrum of human tumor cell lines. BAY 1895344 exhibited strong monotherapy efficacy in cancer xenograft models that carry DNA damage repair deficiencies. The combination of BAY 1895344 with DNA damage-inducing chemotherapy or external beam radiotherapy (EBRT) showed synergistic antitumor activity. Combination treatment with BAY 1895344 and DDR inhibitors achieved strong synergistic antiproliferative activity in vitro, and combined inhibition of ATR and PARP signaling using olaparib demonstrated synergistic antitumor activity in vivo. Furthermore, the combination of BAY 1895344 with the novel, nonsteroidal androgen receptor antagonist darolutamide resulted in significantly improved antitumor efficacy compared with respective singleagent treatments in hormone-dependent prostate cancer, and addition of EBRT resulted in even further enhanced antitumor efficacy. Thus, the ATR inhibitor BAY 1895344 may provide new therapeutic options for the treatment of cancers with certain DDR deficiencies in monotherapy and in combination with DNA damage-inducing or DNA repair-compromising cancer therapies by improving their efficacy.

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“…For chemical structure and additional information about M6620, see ref. 31. Darolutamide was synthesized at Orion Corporation.…”

Section: Compoundsmentioning

confidence: 99%

The Novel ATR Inhibitor BAY 1895344 Is Efficacious as Monotherapy and Combined with DNA Damage–Inducing or Repair–Compromising Therapies in Preclinical Cancer Models

Wengner

Siemeister

Lücking

et al. 2020

Molecular Cancer Therapeutics

145

133

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“…Berzosertib (formerly M6620, VX-970, VE-822) is a selective and potent inhibitor of ataxia-telangiectasia and Rad3related (ATR) for intravenous administration and is being developed in combination with chemotherapy for the treatment of patients with advanced cancers [1,2]. The rationale for clinical development is based on the observation that deoxyribonucleic acid (DNA) damaging drugs and ionizing radiation are widely used as standard of care for the treatment of many solid tumors; however, for many patients, they provide only modest benefit due to highly proficient cellular processes that are able to detect and repair the damaged DNA.…”

Section: Introductionmentioning

confidence: 99%

Population pharmacokinetics of ATR inhibitor berzosertib in phase I studies for different cancer types

Terranova

Jansen²,

Falk

et al. 2020

Cancer Chemother Pharmacol

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Purpose 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. Methods 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/m2). Plasma concentration data were modeled with a non-linear mixed-effect approach and clinical covariates were evaluated. Results 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) IC50 at recommended phase II doses in combination with carboplatin, cisplatin, and gemcitabine. Conclusions 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. Clinical Trial information NCT02157792, EudraCT 2013-005100-34

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“…There are currently four candidates in clinical trials acting as ATR-kinase inhibitors ( Table 1). Two of them were developed by Vertex Pharmaceuticals, Inc., but are presently under maintenance of Merck KGaA (berzosertib and M4344); AstraZeneca PLC and Bayer AG operate with ceralasertib and BAY1895344, respectively [112][113][114][115]. Of these, berzosertib and ceralasertib are the most studied candidates, paving the way for others [116,117].…”

Section: Atr Inhibitors In Clinical Trialsmentioning

confidence: 99%

Clinical Candidates Targeting the ATR–CHK1–WEE1 Axis in Cancer

Górecki

Andrš

Korábečný

2021

Cancers

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Selective killing of cancer cells while sparing healthy ones is the principle of the perfect cancer treatment and the primary aim of many oncologists, molecular biologists, and medicinal chemists. To achieve this goal, it is crucial to understand the molecular mechanisms that distinguish cancer cells from healthy ones. Accordingly, several clinical candidates that use particular mutations in cell-cycle progressions have been developed to kill cancer cells. As the majority of cancer cells have defects in G1 control, targeting the subsequent intra‑S or G2/M checkpoints has also been extensively pursued. This review focuses on clinical candidates that target the kinases involved in intra‑S and G2/M checkpoints, namely, ATR, CHK1, and WEE1 inhibitors. It provides insight into their current status and future perspectives for anticancer treatment. Overall, even though CHK1 inhibitors are still far from clinical establishment, promising accomplishments with ATR and WEE1 inhibitors in phase II trials present a positive outlook for patient survival.

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Rational Design of 5-(4-(Isopropylsulfonyl)phenyl)-3-(3-(4-((methylamino)methyl)phenyl)isoxazol-5-yl)pyrazin-2-amine (VX-970, M6620): Optimization of Intra- and Intermolecular Polar Interactions of a New Ataxia Telangiectasia Mutated and Rad3-Related (ATR) Kinase Inhibitor

Cited by 40 publications

References 43 publications

The Novel ATR Inhibitor BAY 1895344 Is Efficacious as Monotherapy and Combined with DNA Damage–Inducing or Repair–Compromising Therapies in Preclinical Cancer Models

The Novel ATR Inhibitor BAY 1895344 Is Efficacious as Monotherapy and Combined with DNA Damage–Inducing or Repair–Compromising Therapies in Preclinical Cancer Models

Population pharmacokinetics of ATR inhibitor berzosertib in phase I studies for different cancer types

Clinical Candidates Targeting the ATR–CHK1–WEE1 Axis in Cancer

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