| Title: |
Discovery of a selective inhibitor of doublecortin like kinase 1 |
| Authors: |
Ferguson, Fleur M., Nabet, Behnam, Raghavan, Srivatsan, Liu, Yan, Leggett, Alan L., Kuljanin, Miljan, Kalekar, Radha L., Yang, Annan, He, Shuning, Wang, Jinhua, Ng, Raymond W. S., Sulahian, Rita, Li, Lianbo, Poulin, Emily J., Huang, Ling, Koren, Jost, Dieguez-Martinez, Nora, Espinosa, Sergio, Zeng, Zhiyang, Corona, Cesear R., Vasta, James D., Ohi, Ryoma, Sim, Taebo, Kim, Nam Doo, Harshbarger, Wayne, Lizcano, Jose M., Robers, Matthew B., Muthaswamy, Senthil, Lin, Charles Y., Look, A. Thomas, Haigis, Kevin M., Mancias, Joseph D., Wolpin, Brian M., Aguirre, Andrew J., Hahn, William C., Westover, Kenneth D., Gray, Nathanael S. |
| Source: |
Nature Chemical Biology; June 2020, Vol. 16 Issue: 6 p635-643, 9p |
| 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. |
| Database: |
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