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protein kinases - Articles and news items

Shi-Yong Sun

Can mTOR kinase inhibitors beat rapalogues in fighting against cancer?

Cancer Biology, Issue 1 2014 / 19 February 2014 / Shi-Yong Sun, Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute

The mammalian target of rapamycin (mTOR) has emerged as a promising cancer therapeutic target. Some rapamycin analogues (rapalogues) as mTOR allosteric inhibitors are FDA-approved drugs for treatment of certain types of cancers. However, the modest clinical anticancer activity of rapalogues, which preferentially inhibit mTOR complex 1, in most types of cancer, has spurred the development of ATP competitive mTOR kinase inhibitors (TORKinibs) that inhibit both mTOR complex 1 and complex 2, in the hope of developing a novel generation of mTOR inhibitors with better therapeutic efficacy than rapalogues. So far, several TORKinibs have been developed and some are under clinical testing. With a strong rationale, we expect great success in the treatment of cancer with TORKinibs.

Table 1 Three generations of BCR-ABL inhibitor mentioned in this review

Getting to grips with drug resistance in the human protein kinase superfamily

Drug Targets, Issue 1 2013 / 21 February 2013 / Patrick A Eyers, Department of Oncology, Sheffield Cancer Research Centre, University of Sheffield

Protein kinases represent a vast, partially untapped resource of drug targets for therapeutic intervention in human disease. The remarkable success of the tyrosine kinase inhibitor Imatinib, which is now the first-line therapy in Philadelphia-positive tyrosine kinase inhibitor Imatinibhas galvanised biomedical researchers in an attempt to repeat the landmark success of this ‘bench-to-bedside’ approach to therapy[1]. Imatinib inhibits the BCR-ABL fusion kinases responsible for driving these cancers, and its clinical efficacy provides compelling molecular evidence that this drug elicits life-extending clinical responses through an ‘on-target’ mechanism. Interestingly, Imatinib has several additional (non-ABL) protein kinase targets including oncogenic KIT, which also allows it to be employed for the treatment of high-risk Gastro Intestinal Stromal Tumours…

41-51_Figure 7

Conformational Bias: A key concept for protein kinase inhibition

Drug Targets, Issue 1 2012 / 28 February 2012 / Henrik Möbitz, Global Discovery Chemistry, Computer Aided Drug Design, Novartis Institutes for Biomedical Research and Doriano Fabbro, Expertise Platform Kinases, Novartis Institutes for Biomedical Research

Protein kinases act as molecular switches with remarkable plasticity and dynamics upon interaction with specific regulatory domains as well as modulators. Conformation provides a conceptual framework for understanding many aspects of kinase biology. The kinase domain has precise structural prerequisites for signal transfer and can oscillate between two major conformations: an on state with maximal kinase activity (active kinase) and an off state with minimal activity on the other extreme. Conformational bias, i.e. a shift in the equilibrium between active and inactive conformations is a key determinant in kinase regulation and can be brought about by many factors including post-translational modifications, regulatory proteins, ligand binding etc. Kinase inhibitors can be viewed as particular ligands to protein kinases. As the mode of action is linked to the binding mode, the selectivity as well as the kinetics of kinase inhibitors can often be rationalised based on the target conformation. Pathologic kinase deregulation often involves a shift towards the active conformation, leading to constitutive signalling. In this review, we discuss how mutations act as a conformational bias and depending on the mode of action can lead to activation of the protein kinase that can either result in resistance or contribute to the efficacy of kinase inhibitors. Deregulation of protein kinase activities by mutations and/or amplification are associated with a variety of pathologies ranging from cancer to inflammatory diseases, diabetes, infectious diseases and cardiovascular and metabolic disorders…


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