Related Experiment Video

Updated: Oct 19, 2025

Development of Inhibitors of Protein-protein Interactions through REPLACE: Application to the Design and Development Non-ATP Competitive CDK Inhibitors
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Development of Inhibitors of Protein-protein Interactions through REPLACE: Application to the Design and Development Non-ATP Competitive CDK Inhibitors

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

Onisha Patel1,2, Michael J Roy3,4, Ashleigh Kropp3,4

  • 1The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia. patel.o@wehi.edu.au.

Communications Biology
|September 21, 2021
PubMed

Insights

We determined the crystal structures of Doublecortin-like kinase 1 (DCLK1) with its inhibitor DCLK1-IN-1. This reveals how DCLK1-IN-1 selectively targets DCLK1, providing a basis for developing new cancer therapies.

Area of Science:

  • Biochemistry
  • Structural Biology
  • Oncology

Background:

  • Doublecortin-like kinase 1 (DCLK1) is a key kinase implicated in tumor development.
  • Tissue-specific DCLK1 isoforms complicate understanding its role in oncogenesis.
  • DCLK1-IN-1 is a selective inhibitor tool for studying DCLK1 functions.

Purpose of the Study:

  • To elucidate the structural basis of DCLK1 inhibition by DCLK1-IN-1.
  • To understand the structure-activity relationship of DCLK1-IN-1 development.
  • To investigate the impact of DCLK1-IN-1 on DCLK1 isoforms and functions.

Main Methods:

  • X-ray crystallography of DCLK1 kinase domain in complex with DCLK1-IN-1 and precursors.
  • Structural analysis of inhibitor binding and conformational changes.
  • Biochemical assays to assess DCLK1 isoform binding and Microtubule-Associated Protein (MAP) function.

Main Results:

  • Determined crystal structures of DCLK1 kinase domain bound to DCLK1-IN-1.
  • Rationalized the structure-activity relationship and high selectivity of DCLK1-IN-1.
  • Showed DCLK1-IN-1 induces significant conformational changes in the ATP binding site.
  • Demonstrated DCLK1-IN-1 binds long DCLK1 isoforms without inhibiting its MAP function.

Conclusions:

  • The study provides a structural foundation for DCLK1-IN-1's selectivity and mechanism of action.
  • DCLK1-IN-1 offers a valuable tool for dissecting DCLK1 functions in cancer.
  • The findings pave the way for designing isoform-specific DCLK1 modulators for therapeutic applications.

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