Discovery of a selective inhibitor of doublecortin like kinase 1 PMID: 32251410

ADC Targets in Oncology

2026-04-10

Discovery of a selective inhibitor of doublecortin like kinase 1

Nat Chem Biol. 2020 Jun;16(6):635-643. doi: 10.1038/s41589-020-0506-0.

Fleur M Ferguson ^# ¹ ² , Behnam Nabet ^# ¹ ² , Srivatsan Raghavan ³ ⁴ , Yan Liu ⁵ , Alan L Leggett ¹ , Miljan Kuljanin ⁶ , Radha L Kalekar ³ ⁴ , Annan Yang ³ ⁴ , Shuning He ⁷ , Jinhua Wang ¹ ² , Raymond W S Ng ³ ⁴ , Rita Sulahian ⁴ , Lianbo Li ⁵ , Emily J Poulin ⁸ , Ling Huang ⁸ , Jost Koren ⁹ , Nora Dieguez-Martinez ¹⁰ , Sergio Espinosa ¹⁰ , Zhiyang Zeng ¹¹ , Cesear R Corona ¹¹ , James D Vasta ¹¹ , Ryoma Ohi ¹² , Taebo Sim ¹³ , Nam Doo Kim ¹⁴ , Wayne Harshbarger ⁴ ¹⁵ , Jose M Lizcano ¹⁰ , Matthew B Robers ¹¹ , Senthil Muthaswamy ⁸ ¹⁶ , Charles Y Lin ⁹ , A Thomas Look ⁷ ¹⁷ , Kevin M Haigis ⁸ ¹⁸ , Joseph D Mancias ⁶ , Brian M Wolpin ³ ¹⁹ , Andrew J Aguirre ³ ⁴ ¹⁹ , William C Hahn ³ ⁴ ¹⁹ , Kenneth D Westover ⁵ , Nathanael S Gray ²⁰ ²¹

Affiliations

1. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
2. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.
3. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
4. Broad Institute of MIT and Harvard, Cambridge, MA, USA.
5. Departments of Biochemistry and Radiation Oncology, the University of Texas Southwestern Medical Center, Dallas, TX, USA.
6. Division of Radiation and Genome Stability, Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
7. Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
8. Cancer Research Institute and Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
9. Department of Molecular and Human Genetics, Therapeutic Innovation Center Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX, USA.
10. Departament de Bioquímica i Biologia Molecular & Institut de Neurociencies, Facultat de Medicina. Universitat Autonoma de Barcelona, Bellaterra, Spain.
11. Promega Corporation, Madison, WI, USA.
12. Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI, USA.
13. Chemical Kinomics Research Center, Korea Institute of Science and Technology (KIST), Seoul, Republic of Korea and KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul, Republic of Korea.
14. NDBio Therapeutics Inc, Incheon, Republic of Korea.
15. GSK Vaccines, Rockville, MD, USA.
16. Departments of Medicine and Pathology, Harvard Medical School, Boston, MA, USA.
17. Division of Pediatric Hematology/Oncology, Boston Children's Hospital, Boston, MA, USA.
18. Harvard Digestive Disease Center, Harvard Medical School, Boston, MA, USA.
19. Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
20. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA. [email protected].
21. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA. [email protected].
# Contributed equally.

Abstract

Doublecortin Like Kinase 1 (DCLK1) is an understudied kinase that is upregulated in a wide range of cancers, including pancreatic ductal adenocarcinoma (PDAC). However, little is known about its potential as a therapeutic target. We used chemoproteomic profiling and structure-based design to develop a selective, in vivo-compatible chemical probe of the DCLK1 kinase domain, DCLK1-IN-1. We demonstrate activity of DCLK1-IN-1 against clinically relevant patient-derived PDAC Organoid models and use a combination of RNA-sequencing, proteomics and phosphoproteomics analysis to reveal that DCLK1 inhibition modulates proteins and pathways associated with cell motility in this context. DCLK1-IN-1 will serve as a versatile tool to investigate DCLK1 biology and establish its role in Cancer.