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Structural Basis of Inhibition of DCLK1 by Ruxolitinib.
- Source :
-
International journal of molecular sciences [Int J Mol Sci] 2021 Aug 06; Vol. 22 (16). Date of Electronic Publication: 2021 Aug 06. - Publication Year :
- 2021
-
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.
- Subjects :
- Antineoplastic Agents chemistry
Doublecortin-Like Kinases
Humans
Intracellular Signaling Peptides and Proteins chemistry
Intracellular Signaling Peptides and Proteins metabolism
Molecular Docking Simulation
Nitriles
Protein Conformation drug effects
Protein Kinase Inhibitors chemistry
Protein Serine-Threonine Kinases chemistry
Protein Serine-Threonine Kinases metabolism
Pyrazoles chemistry
Pyrimidines
Antineoplastic Agents pharmacology
Intracellular Signaling Peptides and Proteins antagonists & inhibitors
Protein Kinase Inhibitors pharmacology
Protein Serine-Threonine Kinases antagonists & inhibitors
Pyrazoles pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1422-0067
- Volume :
- 22
- Issue :
- 16
- Database :
- MEDLINE
- Journal :
- International journal of molecular sciences
- Publication Type :
- Academic Journal
- Accession number :
- 34445192
- Full Text :
- https://doi.org/10.3390/ijms22168488