7F3G

Crystal structure of DCLK1 kinase domain in complex with ruxolitinib

Summary for 7F3G

• Entry DOI: 10.2210/pdb7f3g/pdb
• Descriptor: Isoform 4 of Serine/threonine-protein kinase DCLK1, (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile (3 entities in total)
• Functional Keywords: doublecortin-like kinase 1, kinase domain, inhibitor, ruxolitinib, signaling protein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 63556.71

Authors

Lim, H.J.,Jang, D.M.,Kim, H.S. (deposition date: 2021-06-16, release date: 2021-08-18, Last modification date: 2023-11-29)

Primary citation

Jang, D.M.,Lim, H.J.,Hahn, H.,Lee, Y.,Kim, H.K.,Kim, H.S.
Structural Basis of Inhibition of DCLK1 by Ruxolitinib.
Int J Mol Sci, 22:-, 2021

PubMed Abstract: Given the functional attributes of Doublecortin-like kinase 1 (DCLK1) in tumor growth, invasion, metastasis, cell motility, and tumor stemness, it is emerging as a therapeutic target in gastrointestinal cancers. Although a series of specific or nonspecific ATP-competitive inhibitors were identified against DCLK1, different types of scaffolds that can be utilized for the development of highly selective inhibitors or structural understanding of binding specificities of the compounds remain limited. Here, we present our work to repurpose a Janus kinase 1 inhibitor, ruxolitinib as a DCLK1 inhibitor, showing micromolar binding affinity and inhibitory activity. Furthermore, to gain an insight into its interaction mode with DCLK1, a crystal structure of the ruxolitinib-complexed DCLK1 has been determined and analyzed. Ruxolitinib as a nonspecific DCLK1 inhibitor characterized in this work is anticipated to provide a starting point for the structure-guided discovery of selective DCLK1 inhibitors.

PubMed: 34445192
DOI: 10.3390/ijms22168488

Experimental method

X-RAY DIFFRACTION (2.1 Å)