ArticleEndocrinology2018
CC-401 Promotes β-Cell Replication via Pleiotropic Consequences of DYRK1A/B Inhibition.
Article in Endocrinology, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 40 papers, 1 of them a synthesis that pooled it.
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Who cites it
40 citing papers in PubMed, 1 synthesis or guideline pooled it, 65 citations in OpenAlex.
- Development and trend of stem cell therapy for diabetes: a comprehensive review based on knowledge visualization.Frontiers in immunology · 2026Pooled it
- Harmine selectively enhances human beta cell identity markers and function via protein kinase A pathways.Diabetologia · 2026Article
- DYRK1A inhibition restores pancreatic functions and improves glucose metabolism in a preclinical model of type 2 diabetes.Molecular metabolism · 2025Article
- Drug-induced regeneration of pancreatic beta cells: An approach to cellular therapeutic targets.Cell regeneration (London, England) · 2025Review
- SPOCK2 controls the proliferation and function of immature pancreatic β-cells through MMP2.Experimental & molecular medicine · 2025Article
- Harnessing beta-cell replication: advancing molecular insights to regenerative therapies in diabetes.Frontiers in endocrinology · 2025Review
- Cycling alpha cells in regenerative drug-treated human pancreatic islets may serve as key beta cell progenitors.Cell reports. Medicine · 2024Article
- Scaling Insulin-Producing Cells by Multiple Strategies.Endocrinology and metabolism (Seoul, Korea) · 2024Review
- CaBiomedicines · 2023Review
- Regeneration of Pancreatic β-Cells for Diabetes Therapeutics by Natural DYRK1A Inhibitors.Metabolites · 2022Review
- Disrupting the DREAM complex enables proliferation of adult human pancreatic β cells.The Journal of clinical investigation · 2022Article
- β-Cell Succinate Dehydrogenase Deficiency Triggers Metabolic Dysfunction and Insulinopenic Diabetes.Diabetes · 2022Article
- Small-molecule discovery in the pancreatic beta cell.Current opinion in chemical biology · 2022Review
- Evaluation of the Effects of Harmine on β-cell Function and Proliferation in Standardized Human Islets Using 3D High-Content Confocal Imaging and Automated Analysis.Frontiers in endocrinology · 2022Review
- Identification of direct transcriptional targets of NFATC2 that promote β cell proliferation.The Journal of clinical investigation · 2021Article
- Article
- Diabetic Kinome Inhibitors-A New Opportunity for β-Cells Restoration.International journal of molecular sciences · 2021Review
- Silencing the G-protein coupled receptor 3-salt inducible kinase 2 pathway promotes human β cell proliferation.Communications biology · 2021Article
- The small molecule kobusone can stimulate islet β-cell replicationThe Journal of international medical research · 2021Article
- A natural DYRK1A inhibitor as a potential stimulator for β-cell proliferation in diabetes.Clinical and translational medicine · 2021Article
Corrections and comments
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Authors and funding
14 authors at 2 institutions in 1 country.
Funding
Abstract
Pharmacologic expansion of endogenous β cells is a promising therapeutic strategy for diabetes. To elucidate the molecular pathways that control β-cell growth we screened ∼2400 bioactive compounds for rat β-cell replication-modulating activity. Numerous hit compounds impaired or promoted rat β-cell replication, including CC-401, an advanced clinical candidate previously characterized as a c-Jun N-terminal kinase inhibitor. Surprisingly, CC-401 induced rodent (in vitro and in vivo) and human (in vitro) β-cell replication via dual-specificity tyrosine phosphorylation-regulated kinase (DYRK) 1A and 1B inhibition. In contrast to rat β cells, which were broadly growth responsive to compound treatment, human β-cell replication was only consistently induced by DYRK1A/B inhibitors. This effect was enhanced by simultaneous glycogen synthase kinase-3β (GSK-3β) or activin A receptor type II-like kinase/transforming growth factor-β (ALK5/TGF-β) inhibition. Prior work emphasized DYRK1A/B inhibition-dependent activation of nuclear factor of activated T cells (NFAT) as the primary mechanism of human β-cell-replication induction. However, inhibition of NFAT activity had limited effect on CC-401-induced β-cell replication. Consequently, we investigated additional effects of CC-401-dependent DYRK1A/B inhibition. Indeed, CC-401 inhibited DYRK1A-dependent phosphorylation/stabilization of the β-cell-replication inhibitor p27Kip1. Additionally, CC-401 increased expression of numerous replication-promoting genes normally suppressed by the dimerization partner, RB-like, E2F and multivulval class B (DREAM) complex, which depends upon DYRK1A/B activity for integrity, including MYBL2 and FOXM1. In summary, we present a compendium of compounds as a valuable resource for manipulating the signaling pathways that control β-cell replication and leverage a DYRK1A/B inhibitor (CC-401) to expand our understanding of the molecular pathways that control β-cell growth.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.