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Progress towards a public chemogenomic set for protein kinases and a call for contributions.

ABSTRACT: Protein kinases are highly tractable targets for drug discovery. However, the biological function and therapeutic potential of the majority of the 500+ human protein kinases remains unknown. We have developed physical and virtual collections of small molecule inhibitors, which we call chemogenomic sets, that are designed to inhibit the catalytic function of almost half the human protein kinases. In this manuscript we share our progress towards generation of a comprehensive kinase chemogenomic set (KCGS), release kinome profiling data of a large inhibitor set (Published Kinase Inhibitor Set 2 (PKIS2)), and outline a process through which the community can openly collaborate to create a KCGS that probes the full complement of human protein kinases.

SUBMITTER: Drewry DH

PROVIDER: S-EPMC5540273 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Progress towards a public chemogenomic set for protein kinases and a call for contributions.

Drewry David H DH Wells Carrow I CI Andrews David M DM Angell Richard R Al-Ali Hassan H Axtman Alison D AD Capuzzi Stephen J SJ Elkins Jonathan M JM Ettmayer Peter P Frederiksen Mathias M Gileadi Opher O Gray Nathanael N Hooper Alice A Knapp Stefan S Laufer Stefan S Luecking Ulrich U Michaelides Michael M Müller Susanne S Muratov Eugene E Denny R Aldrin RA Saikatendu Kumar S KS Treiber Daniel K DK Zuercher William J WJ Willson Timothy M TM

PloS one 20170802 8

Protein kinases are highly tractable targets for drug discovery. However, the biological function and therapeutic potential of the majority of the 500+ human protein kinases remains unknown. We have developed physical and virtual collections of small molecule inhibitors, which we call chemogenomic sets, that are designed to inhibit the catalytic function of almost half the human protein kinases. In this manuscript we share our progress towards generation of a comprehensive kinase chemogenomic se ...[more]

PMID: 28767711

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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.

Dataset Information

Progress towards a public chemogenomic set for protein kinases and a call for contributions.

Publications

Progress towards a public chemogenomic set for protein kinases and a call for contributions.

Similar Datasets

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