6K0J
The co-crystal structure of DYRK2 with a small molecule inhibitor
Summary for 6K0J
| Entry DOI | 10.2210/pdb6k0j/pdb |
| Descriptor | Dual specificity tyrosine-phosphorylation-regulated kinase 2, 3-(2,7-dimethoxyacridin-9-yl)sulfanylpropan-1-amine (3 entities in total) |
| Functional Keywords | kinase, transferase-inhibitor complex, transferase/inhibitor |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 1 |
| Total formula weight | 38099.10 |
| Authors | Tiantian, W.,Xiao, J. (deposition date: 2019-05-06, release date: 2019-11-20, Last modification date: 2024-11-13) |
| Primary citation | Banerjee, S.,Wei, T.,Wang, J.,Lee, J.J.,Gutierrez, H.L.,Chapman, O.,Wiley, S.E.,Mayfield, J.E.,Tandon, V.,Juarez, E.F.,Chavez, L.,Liang, R.,Sah, R.L.,Costello, C.,Mesirov, J.P.,de la Vega, L.,Cooper, K.L.,Dixon, J.E.,Xiao, J.,Lei, X. Inhibition of dual-specificity tyrosine phosphorylation-regulated kinase 2 perturbs 26S proteasome-addicted neoplastic progression. Proc.Natl.Acad.Sci.USA, 116:24881-24891, 2019 Cited by PubMed Abstract: Dependence on the 26S proteasome is an Achilles' heel for triple-negative breast cancer (TNBC) and multiple myeloma (MM). The therapeutic proteasome inhibitor, bortezomib, successfully targets MM but often leads to drug-resistant disease relapse and fails in breast cancer. Here we show that a 26S proteasome-regulating kinase, DYRK2, is a therapeutic target for both MM and TNBC. Genome editing or small-molecule mediated inhibition of DYRK2 significantly reduces 26S proteasome activity, bypasses bortezomib resistance, and dramatically delays in vivo tumor growth in MM and TNBC thereby promoting survival. We further characterized the ability of LDN192960, a potent and selective DYRK2-inhibitor, to alleviate tumor burden in vivo. The drug docks into the active site of DYRK2 and partially inhibits all 3 core peptidase activities of the proteasome. Our results suggest that targeting 26S proteasome regulators will pave the way for therapeutic strategies in MM and TNBC. PubMed: 31754034DOI: 10.1073/pnas.1912033116 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.352 Å) |
Structure validation
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