Journal article

Structural basis for small molecule targeting of Doublecortin Like Kinase 1 with DCLK1-IN-1

Onisha Patel, Michael J Roy, Ashleigh Kropp, Joshua M Hardy, Weiwen Dai, Isabelle S Lucet



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 bas..

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Awarded by ARC Future Fellowship

Awarded by National Health and Medical Research Council, Australia

Funding Acknowledgements

O.P. was supported by an ARC Future Fellowship (FT120100056). I.L. acknowledges the support from the Walter and Eliza Hall Institute. This work was supported by the National Health and Medical Research Council, Australia (Project Grant APP1162058) with additional support from the Victorian State Government Operational Infrastructure Support Programme and from the Australian Cancer Research Foundation (to I.L., W.D., O.P., A.K., M.R.). We acknowledge Melbourne Research Scholarship support for A.K. from the University of Melbourne. We would like to thank the staff at the Bio21 C3 Collaborative Crystallisation Centre where all initial crystallisation experiments were performed. This research was undertaken in part using the MX2 beamline at the Australian Synchrotron, part of ANSTO, and made use of the Australian Cancer Research Foundation (ACRF) detector. We would like to thank the staff at the Australian Synchrotron. We would also like to thank Nathanael Gray and Fleur Ferguson for providing the DCLK1 compounds.