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The central role of dysregulated kinase activity in the etiology of progressive disorders, including cancer, has fostered incremental efforts on drug discovery programs over the last 40 years. As a result, kinase inhibitors are today one of the most important classes of drugs. The FDA approved 72 small molecule kinase inhibitor drugs until Aug 2021, and additional inhibitors were approvedby other regulatory agencies during that time. To complement the published literature on clinical kinase inhibitors, we have prepared a review that recaps this large dataset into an accessible format for the medicinal chemistry community. Along with the therapeutic and pharmacological properties of each kinase inhibitor approved across the world until 2020, we provide the synthesisroutes originally used during the discovery phase, many of which were only available in patent applications. In the last section, we also provide an update on kinase inhibitor drugs approved in2021.

C. Temps thanks the CMVM of the University of Edinburgh (Principal's scholarship). D. Lietha acknowledges support from the Spanish Ministry of Science, Innovation, and Universities for the Spanish State Research Agency Retos Grant RTI2018-099318-B-I00, cofunded by the European Regional Development Fund (FEDER). E.R. Webb, J.C. Dawson, and K.G. Macleod are funded by CRUK. J.R. Luque-Ortega acknowledges support from the Molecular Interactions Facility funds at the CIB-CSIC. T. Valero is funded by H2020-MSCA-IF-2016-749299. R. Contreras-Montoya thanks the support from the Vice-Rectorate for Research of the University of Granada. X-F. Li and B-Z. Qian are funded by a CRUK Career Development Fellowship (C49791/A17367). B-Z. Qian also acknowledges support from an ERC Starting Grant (716379). C. Schoenherr, M.C. Frame, and V.G. Brunton are funded by CRUK Programme Grant C157/A15703. N.O. Carragher and A. Unciti-Broceta are grateful to the CMVM of the University of Edinburgh and Wellcome Trust for financial support (ISSF3). We thank the ALBA synchrotron-radiation facility (Barcelona, Spain) for providing access for X-ray diffraction data collection and the XALOC beamline staff for their assistance., Despite the approval of several multikinase inhibitors that target SRC and the overwhelming evidence of the role of SRC in the progression and resistance mechanisms of many solid malignancies, inhibition of its kinase activity has thus far failed to improve patient outcomes. Here we report the small molecule eCF506 locks SRC in its native inactive conformation, thereby inhibiting both enzymatic and scaffolding functions that prevent phosphorylation and complex formation with its partner FAK. This mechanism of action resulted in highly potent and selective pathway inhibition in culture and in vivo. Treatment with eCF506 resulted in increased antitumor efficacy and tolerability in syngeneic murine cancer models, demonstrating significant therapeutic advantages over existing SRC/ABL inhibitors. Therefore, this mode of inhibiting SRC could lead to improved treatment of SRC-associated disorders. Significance: Small molecule–mediated inhibition of SRC impairing both catalytic and scaffolding functions confers increased anticancer properties and tolerability compared with other SRC/ABL inhibitors., Spanish Ministry of Science, Innovation, and Universities RTI2018-099318-B-I00, European Commission, Cancer Research UK, Molecular Interactions Facility funds at the CIB-CSIC, Vice-Rectorate for Research of the University of Granada, CRUK Career Development Fellowship C49791/A17367, European Research Council (ERC) 716379, CRUK Programme Grant C157/A15703, CMVM of the University of Edinburgh, Wellcome Trust, European Commission H2020-MSCA-IF-2016-749299