2. Academic Validation
  3. Selective DYRK1A Inhibitor for the Treatment of Type 1 Diabetes: Discovery of 6-Azaindole Derivative GNF2133

Selective DYRK1A Inhibitor for the Treatment of Type 1 Diabetes: Discovery of 6-Azaindole Derivative GNF2133

  • J Med Chem. 2020 Mar 26;63(6):2958-2973. doi: 10.1021/acs.jmedchem.9b01624.
Yahu A Liu 1,  Qihui Jin 1,  Yefen Zou 1,  Qiang Ding 1,  Shanshan Yan 1,  Zhicheng Wang 1,  Xueshi Hao 1,  Bao Nguyen 1,  Xiaoyue Zhang 1,  Jianfeng Pan 1,  Tingting Mo 1,  Kate Jacobsen 1,  Thanh Lam 1,  Tom Y-H Wu 1,  H Michael Petrassi 1,  Badry Bursulaya 1,  Michael DiDonato 1,  W Perry Gordon 1,  Bo Liu 1,  Janine Baaten 1,  Robert Hill 1,  Vân Nguyen-Tran 1,  Minhua Qiu 1,  You-Qing Zhang 1,  Anwesh Kamireddy 1,  Sheryll Espinola 1,  Lisa Deaton 1,  Sukwon Ha 1,  George Harb 1,  Yong Jia 1,  Jing Li 1,  Weijun Shen 1,  Andrew M Schumacher 1,  Karyn Colman 1,  Richard Glynne 1,  Shifeng Pan 1,  Peter McNamara 1,  Bryan Laffitte 1,  Shelly Meeusen 1,  Valentina Molteni 1,  Jon Loren 1
Affiliations

Affiliation

  • 1 Genomics Institute of the Novartis Research Foundation (GNF), 10675 John Jay Hopkins Drive, San Diego, California 92121, United States.
PMID: 32077280 DOI: 10.1021/acs.jmedchem.9b01624
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. In vitro, GNF2133 is able to proliferate both rodent and human β-cells. In vivo, 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).

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