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Publication Abstract from PubMed

Doublecortin-like kinase 1 (DCLK1) is an understudied bi-functional kinase with a proven role in tumour growth and development. However, the presence of tissue-specific spliced DCLK1 isoforms with distinct biological functions have challenged the development of effective strategies to understand the role of DCLK1 in oncogenesis. Recently, DCLK1-IN-1 was reported as a highly selective DCLK1 inhibitor, a powerful tool to dissect DCLK1 biological functions. Here, we report the crystal structures of DCLK1 kinase domain in complex with DCLK1-IN-1 and its precursors. Combined, our data rationalises the structure-activity relationship that informed the development of DCLK1-IN-1 and provides the basis for the high selectivity of DCLK1-IN-1, with DCLK1-IN-1 inducing a drastic conformational change of the ATP binding site. We demonstrate that DCLK1-IN-1 binds DCLK1 long isoforms but does not prevent DCLK1's Microtubule-Associated Protein (MAP) function. Together, our work provides an invaluable structural platform to further the design of isoform-specific DCLK1 modulators for therapeutic intervention.

Structural basis for small molecule targeting of Doublecortin Like Kinase 1 with DCLK1-IN-1.,Patel O, Roy MJ, Kropp A, Hardy JM, Dai W, Lucet IS Commun Biol. 2021 Sep 20;4(1):1105. doi: 10.1038/s42003-021-02631-y. PMID:34545159^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.