ABSTRACT
The rising prevalence of diabetes is threatening global health. It is known not only for the occurrence of severe complications but also for the SARS-Cov-2 pandemic, which shows that it exacerbates susceptibility to infections. Current therapies focus on artificially maintaining insulin homeostasis, and a durable cure has not yet been achieved. We demonstrate that our set of small molecule inhibitors of DYRK1A kinase potently promotes ß-cell proliferation, enhances long-term insulin secretion, and balances glucagon level in the organoid model of the human islets. Comparable activity is seen in INS-1E and MIN6 cells, in isolated mice islets, and human iPSC-derived ß-cells. Our compounds exert a significantly more pronounced effect compared to harmine, the best-documented molecule enhancing ß-cell proliferation. Using a body-like environment of the organoid, we provide a proof-of-concept that small-molecule-induced human ß-cell proliferation via DYRK1A inhibition is achievable, which lends a considerable promise for regenerative medicine in T1DM and T2DM treatment.
Subject(s)
Homeostasis , Insulin-Secreting Cells/cytology , Insulin-Secreting Cells/enzymology , Insulin/metabolism , Protein Kinase Inhibitors/pharmacology , Protein Serine-Threonine Kinases/antagonists & inhibitors , Protein-Tyrosine Kinases/antagonists & inhibitors , Animals , Cell Line , Cell Proliferation/drug effects , Cell Survival/drug effects , Genes, Reporter , Harmine/pharmacology , Homeostasis/drug effects , Humans , Induced Pluripotent Stem Cells/drug effects , Induced Pluripotent Stem Cells/metabolism , Insulin-Secreting Cells/drug effects , Kinetics , Male , Mice , Models, Biological , NFATC Transcription Factors/metabolism , Organoids/drug effects , Organoids/metabolism , Protein Kinase Inhibitors/chemistry , Protein Serine-Threonine Kinases/metabolism , Protein-Tyrosine Kinases/metabolism , Rats , Transforming Growth Factor beta/antagonists & inhibitors , Transforming Growth Factor beta/metabolism , Dyrk KinasesABSTRACT
A series of novel 4-butyl-arylpiperazine-3-(1H-indol-3-yl)pyrrolidine-2,5-dione derivatives were synthesized and evaluated for their 5-HT1A/D2 receptor affinity and serotonin reuptake inhibition. The compounds exhibited high affinity for the 5-HT1A receptor, (especially 4dKi = 0.4 nM) which depended on the substitution pattern at the phenylpiperazine moiety. From this series screen, compound 4c emerged with promising mixed receptor profiles for the 5-HT1A/D2 receptors and the serotonin transporter (Ki = 1.3 nM, 182 nM and 64 nM, respectively).