title: Function through bio-inspired, synthesis-informed design: step-economical syntheses of designed kinase inhibitors†Dedicated to Max Malacria, a friend and scholar whose science and creative contributions to step-economical synthesis have inspired us all and moved the field closer to the ideal.‡Electronic supplementary information (ESI) available: Synthetic procedures and spectral data. See DOI: 10.1039/c4qo00228hClick here for additional data file.
abstract: The human kinome comprises over 500 protein kinases. When mutated or over-expressed, many play critical roles in abnormal cellular functions associated with cancer, cardiovascular disease and neurological disorders. Here we report a step-economical approach to designed kinase inhibitors inspired by the potent, but non-selective, natural product staurosporine, and synthetically enabled by a novel, complexity-increasing, serialized [5 + 2]/[4 + 2] cycloaddition strategy. This function-oriented synthesis approach rapidly affords tunable scaffolds, and produced a low nanomolar inhibitor of protein kinase C.
authors: Department of Chemistry and Department of Chemical and Systems Biology , Stanford University , Stanford , CA 94305 , USA . Email: wenderp@stanford.edu.
authors: Paul A
authors: PA
authors: Wender
authors: Department of Chemistry and Department of Chemical and Systems Biology , Stanford University , Stanford , CA 94305 , USA . Email: wenderp@stanford.edu.
authors: Alison D
authors: AD
authors: Axtman
authors: Department of Chemistry and Department of Chemical and Systems Biology , Stanford University , Stanford , CA 94305 , USA . Email: wenderp@stanford.edu.
authors: Jennifer E
authors: JE
authors: Golden
authors: Department of Chemistry and Department of Chemical and Systems Biology , Stanford University , Stanford , CA 94305 , USA . Email: wenderp@stanford.edu.
authors: Jung-Min
authors: JM
authors: Kee
authors: Department of Chemistry and Department of Chemical and Systems Biology , Stanford University , Stanford , CA 94305 , USA . Email: wenderp@stanford.edu.
authors: Lauren E
authors: LE
authors: Sirois
authors: Department of Chemistry and Department of Chemical and Systems Biology , Stanford University , Stanford , CA 94305 , USA . Email: wenderp@stanford.edu.
authors: Ryan V
authors: RV
authors: Quiroz
authors: Department of Chemistry and Department of Chemical and Systems Biology , Stanford University , Stanford , CA 94305 , USA . Email: wenderp@stanford.edu.
authors: Matthew C
authors: MC
authors: Stevens
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