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Progress towards a clinically-successful ATR inhibitor for cancer therapy.

ABSTRACT: The DNA damage response (DDR) is now known to play an important role in both cancer development and its treatment. Targeting proteins such as ATR (Ataxia telangiectasia mutated and Rad3-related) kinase, a major regulator of DDR, has demonstrated significant therapeutic potential in cancer treatment, with ATR inhibitors having shown anti-tumour activity not just as monotherapies, but also in potentiating the effects of conventional chemotherapy, radiotherapy, and immunotherapy. This review focuses on the biology of ATR, its functional role in cancer development and treatment, and the rationale behind inhibition of this target as a therapeutic approach, including evaluation of the progress and current status of development of potent and specific ATR inhibitors that have emerged in recent decades. The current applications of these inhibitors both in preclinical and clinical studies either as single agents or in combinations with chemotherapy, radiotherapy and immunotherapy are also extensively discussed. This review concludes with some insights into the various concerns raised or observed with ATR inhibition in both the preclinical and clinical settings, with some suggested solutions.

SUBMITTER: Barnieh FM

PROVIDER: S-EPMC8663972 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Progress towards a clinically-successful ATR inhibitor for cancer therapy.

Barnieh Francis M FM Loadman Paul M PM Falconer Robert A RA

Current research in pharmacology and drug discovery 20210205

The DNA damage response (DDR) is now known to play an important role in both cancer development and its treatment. Targeting proteins such as ATR (Ataxia telangiectasia mutated and Rad3-related) kinase, a major regulator of DDR, has demonstrated significant therapeutic potential in cancer treatment, with ATR inhibitors having shown anti-tumour activity not just as monotherapies, but also in potentiating the effects of conventional chemotherapy, radiotherapy, and immunotherapy. This review focuse ...[more]

PMID: 34909652

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Project description:Dr. John Herrick described the first clinical case of sickle cell anaemia (SCA) in the United States in 1910. Subsequently, four decades later, Ingram and colleagues characterized the A to T substitution in DNA producing the GAG to GTG codon and replacement of glutamic acid with valine in the sixth position of the βS -globin chain. The establishment of Comprehensive Sickle Cell Centers in the United States in the 1970s was an important milestone in the development of treatment strategies and describing the natural history of sickle cell disease (SCD) comprised of genotypes including homozygous haemoglobin SS (HbSS), HbSβ0 thalassaemia, HbSC and HbSβ+ thalassaemia, among others. Early drug studies demonstrating effective treatments of HbSS and HbSβ0 thalassaemia, stimulated clinical trials to develop disease-specific therapies to induce fetal haemoglobin due to its ability to block HbS polymerization. Subsequently, hydroxycarbamide proved efficacious in adults with SCA and was Food and Drug Administration (FDA)-approved in 1998. After two decades of hydroxycarbamide use for SCD, there continues to be limited clinical acceptance of this chemotherapy drug, providing the impetus for investigators and pharmaceutical companies to develop non-chemotherapy agents. Investigative efforts to determine the role of events downstream of deoxy-HbS polymerization, such as endothelial cell activation, cellular adhesion, chronic inflammation, intravascular haemolysis and nitric oxide scavenging, have expanded drug targets which reverse the pathophysiology of SCD. After two decades of slow progress in the field, since 2018 three new drugs were FDA-approved for SCA, but research efforts to develop treatments continue. Currently over 30 treatment intervention trials are in progress to investigate a wide range of agents acting by complementary mechanisms, providing the rationale for ushering in the age of effective and safe combination drug therapy for SCD. Parallel efforts to develop curative therapies using haematopoietic stem cell transplant and gene therapy provide individuals with SCD multiple treatment options. We will discuss progress made towards drug development and potential combination drug therapy for SCD with the standard of care hydroxycarbamide.

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Dataset Information

Progress towards a clinically-successful ATR inhibitor for cancer therapy.

Publications

Progress towards a clinically-successful ATR inhibitor for cancer therapy.

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