6UIP

DYRK1A Kinase Domain in Complex with a 6-azaindole Derivative, GNF2133.

Summary for 6UIP

• Entry DOI: 10.2210/pdb6uip/pdb
• Descriptor: Dual specificity tyrosine-phosphorylation-regulated kinase 1A, 4-ethyl-N-{4-[1-(oxan-4-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl]pyridin-2-yl}piperazine-1-carboxamide (2 entities in total)
• Functional Keywords: kinase, inhibitor, transferase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 3
• Total formula weight: 127548.21

Authors

DiDonato, M.,Spraggon, G. (deposition date: 2019-10-01, release date: 2020-03-04, Last modification date: 2024-10-30)

Primary citation

Liu, Y.A.,Jin, Q.,Zou, Y.,Ding, Q.,Yan, S.,Wang, Z.,Hao, X.,Nguyen, B.,Zhang, X.,Pan, J.,Mo, T.,Jacobsen, K.,Lam, T.,Wu, T.Y.,Petrassi, H.M.,Bursulaya, B.,DiDonato, M.,Gordon, W.P.,Liu, B.,Baaten, J.,Hill, R.,Nguyen-Tran, V.,Qiu, M.,Zhang, Y.Q.,Kamireddy, A.,Espinola, S.,Deaton, L.,Ha, S.,Harb, G.,Jia, Y.,Li, J.,Shen, W.,Schumacher, A.M.,Colman, K.,Glynne, R.,Pan, S.,McNamara, P.,Laffitte, B.,Meeusen, S.,Molteni, V.,Loren, J.
Selective DYRK1A Inhibitor for the Treatment of Type 1 Diabetes: Discovery of 6-Azaindole Derivative GNF2133.
J.Med.Chem., 63:2958-2973, 2020

PubMed Abstract: Autoimmune deficiency and destruction in either β-cell mass or function can cause insufficient insulin levels and, as a result, hyperglycemia and diabetes. Thus, promoting β-cell proliferation could be one approach toward diabetes intervention. In this report we describe the discovery of a potent and selective DYRK1A inhibitor GNF2133, which was identified through optimization of a 6-azaindole screening hit. , GNF2133 is able to proliferate both rodent and human β-cells. , GNF2133 demonstrated significant dose-dependent glucose disposal capacity and insulin secretion in response to glucose-potentiated arginine-induced insulin secretion (GPAIS) challenge in rat insulin promoter and diphtheria toxin A (RIP-DTA) mice. The work described here provides new avenues to disease altering therapeutic interventions in the treatment of type 1 diabetes (T1D).

PubMed: 32077280
DOI: 10.1021/acs.jmedchem.9b01624

Experimental method

X-RAY DIFFRACTION (3.7 Å)