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
  • 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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