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  • br The future of cancer therapeutics with

    2023-01-28


    The future of cancer therapeutics with Aurora kinase inhibitors Involvement of Aurora kinases in deregulating multiple tumor suppressor and oncogenic pathways together with the preclinical findings on the efficacy of Aurora kinase inhibitors in attenuating growth of tumor flavopiridol synthesis suggests that these molecules hold the promise of being developed into effective anticancer drugs in the future. Whether such inhibitors will be effective on their own or in combination with additional drugs targeting other oncogenic deregulated pathways would be decided based on the outcomes of the trials currently underway. The results of these trials will also reveal if tumors initially responding to the drugs acquire clinical resistance on prolonged treatment. The ability of cancer cells to acquire clinical resistance to therapeutic inhibitors is generally associated with mutations in their target protein encoding genes which impair inhibitor binding and this may be encountered in case of Aurora kinase inhibitors as well. Mutation in the oncogenic fusion protein Bcr-Abl tyrosine kinase in leukemia is one such example that makes the disease resistant to therapeutic inhibitors targeting the kinase. Imatinib was the first approved ATP-competitive inhibitor against Bcr-Abl kinase that improved survival of 95% of CML patients when treated during the chronic phase of a disease whereas treatment initiated during blast phase occasionally led to imatinib-resistance [102], [103]. Over 50 mutations in the Abl kinase domain have so far been implicated in resistance to imatinib [104]. Dasatinib and nilotinib, the second generation inhibitors, targeting imatinib-resistant mutants of Bcr-Abl kinase were developed soon after identification of the mutations and treatment with these compounds have yielded encouraging clinical outcomes. However, treatment with these inhibitors results in compound kinase domain mutations that render patients resistant to multiple inhibitors, demonstrating remarkable plasticity of Abl kinase domain and potential hazards of sequential kinase inhibitor treatment [53]. As mentioned earlier, Aurora kinase inhibitors have shown efficacy in the treatment of leukemias expressing clinically resistant mutants of Bcr-Abl. Kinase. Although combinations of different BCR-ABL kinase inhibitors and Aurora kinase inhibitors such as VX-680/MK-0457 and VE-465 might constitute more effective therapeutic regimens for treating Bcr-Abl expressing leukemia, the prospect of long term efficacy of such treatment strategies will be known after additional clinical trials in the future. To circumvent the problems encountered in case of ATP-competitive inhibitors, two alternative approaches are worthy of consideration. One strategy is to find novel inhibitor molecules that inhibit kinase activity by an allosteric non-ATP-competitive mechanism and the other is to develop inhibitors that interfere with substrate recognition of the target kinase. GNF2 and GNF-5, an analogue of GNF2 were recently identified as allosteric inhibitors of Bcr-Abl that bind to myristate-binding site located near the C-terminus of Abl kinase domain resulting in a conformational change at the ATP-binding site with loss of kinase activity. These two inhibitors can act cooperatively with imatinib to inhibit both wild type and mutant Bcr-Abl, indicating that treatment with combined allosteric and ATP-competitive inhibitors is possibly an effective way to overcome clinical resistance in mutant kinase expressing refractory disease [105], [106]. A number of allosteric inhibitors have also been developed for multiple kinases including Akt and IkB kinase [107], [108].
    Acknowledgements We apologize to those investigators whose work has not been discussed due to space limitations. Work in the author's lab is supported by grants from the National Institutes of Health (RO1CA089716) and University Cancer Foundation grants from UTMDACC to S.S.