6UWY
DYRK1A bound to a harmine derivative
Summary for 6UWY
| Entry DOI | 10.2210/pdb6uwy/pdb |
| Descriptor | Dual specificity tyrosine-phosphorylation-regulated kinase 1A, 4-(7-methoxy-1-methyl-9H-beta-carbolin-9-yl)butanamide, TETRAETHYLENE GLYCOL, ... (4 entities in total) |
| Functional Keywords | kinase, transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 4 |
| Total formula weight | 171652.03 |
| Authors | Khamrui, S.,Lazarus, M.B. (deposition date: 2019-11-05, release date: 2020-02-12, Last modification date: 2024-11-13) |
| Primary citation | Kumar, K.,Wang, P.,Wilson, J.,Zlatanic, V.,Berrouet, C.,Khamrui, S.,Secor, C.,Swartz, E.A.,Lazarus, M.,Sanchez, R.,Stewart, A.F.,Garcia-Ocana, A.,DeVita, R.J. Synthesis and Biological Validation of a Harmine-Based, Central Nervous System (CNS)-Avoidant, Selective, Human beta-Cell Regenerative Dual-Specificity Tyrosine Phosphorylation-Regulated Kinase A (DYRK1A) Inhibitor. J.Med.Chem., 63:2986-3003, 2020 Cited by PubMed Abstract: Recently, our group identified that harmine is able to induce β-cell proliferation both in vitro and in vivo, mediated via the DYRK1A-NFAT pathway. Since, harmine suffers from a lack of selectivity, both against other kinases and CNS off-targets, we therefore sought to expand structure-activity relationships for harmine's DYRK1A activity, to enhance selectivity for off-targets while retaining human β-cell proliferation activity. We carried out optimization of the 9--position of harmine to synthesize 29 harmine-based analogs. Several novel inhibitors showed excellent DYRK1A inhibition and human β-cell proliferation capability. An optimized DYRK1A inhibitor, , was identified as a novel, efficacious in vivo lead candidate. also demonstrates improved selectivity for kinases and CNS off-targets, as well as in vivo efficacy for β-cell proliferation and regeneration at lower doses than harmine. Collectively, these findings demonstrate that is a much improved in vivo lead candidate as compared to harmine for the treatment of diabetes. PubMed: 32003560DOI: 10.1021/acs.jmedchem.9b01379 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.95 Å) |
Structure validation
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