8HLT

The co-crystal structure of DYRK2 with YK-2-99B

Summary for 8HLT

• Entry DOI: 10.2210/pdb8hlt/pdb
• Descriptor: Dual specificity tyrosine-phosphorylation-regulated kinase 2, (6-{[(4P)-4-(1,3-benzothiazol-5-yl)-5-fluoropyrimidin-2-yl]amino}pyridin-3-yl)(piperazin-1-yl)methanone (2 entities in total)
• Functional Keywords: inhibitor, cell cycle
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 91387.48

Authors

Shen, H.T.,Xiao, Y.B.,Yuan, K.,Yang, P.,Li, Q.N. (deposition date: 2022-12-01, release date: 2023-12-13, Last modification date: 2024-10-23)

Primary citation

Yuan, K.,Shen, H.,Zheng, M.,Xia, F.,Li, Q.,Chen, W.,Ji, M.,Yang, H.,Zhuang, X.,Cai, Z.,Min, W.,Wang, X.,Xiao, Y.,Yang, P.
Discovery of Potent DYRK2 Inhibitors with High Selectivity, Great Solubility, and Excellent Safety Properties for the Treatment of Prostate Cancer.
J.Med.Chem., 66:4215-4230, 2023

PubMed Abstract: Prostate cancer (PCa) is a common male cancer with high incidence and mortality, and hormonal therapy as the major treatment for PCa patients is troubled by the inevitable resistance that makes us identify novel targets for PCa. Dual-specificity tyrosine phosphorylation-regulated kinase 2 (DYRK2) was found to be an effective target for the treatment of PCa, but the research on its inhibitors is rather little. In this work, a potent DYRK2 inhibitor (IC = 0.6 nM) was acquired through virtual screening and structural optimization, which displayed high selectivity among 205 kinases; meanwhile, detailed interactions of with DYRK2 were illustrated by the cocrystal. Furthermore, possessed great water solubility (29.5 mg/mL), favorable safety properties (LD > 10,000 mg/kg), and potent anti-PCa activities, which could be used as a potential candidate in further preclinical studies.

PubMed: 36800260
DOI: 10.1021/acs.jmedchem.3c00106

Experimental method

X-RAY DIFFRACTION (2.8 Å)