A novel small molecule inhibitor of p38⍺ MAP kinase augments cardiomyocyte cell cycle entry in response to direct cell cycle stimulation

• Published in: British journal of pharmacology Vol. 180; no. 24; p. 3271
• Main Authors: Abouleisa, Riham R E, Miller, Jessica M, Gebreil, Ahmad, Salama, Abou Bakr M, Dwenger, Marc, Abdelhafez, Hania, Wahid, Reham M, Adewumi, Adeniyi T, Soliman, Mahmoud E S, Abo-Dya, Nader E, Mohamed, Tamer M A
• Format: Journal Article
• Language: English
• Published: England 01.12.2023
• Subjects: Animals; Cell Cycle; Cell Division; Enzyme Inhibitors - pharmacology; Humans; Mammals - metabolism; Mitogen-Activated Protein Kinases - metabolism; Myocytes, Cardiac - metabolism; p38 Mitogen-Activated Protein Kinases - metabolism; small molecule; cyclin; P38; proliferation; cell cycle; cardiomyocyte; autodock; heart
• ISSN: 1476-5381
• DOI: 10.1111/bph.16209

Myocardial infarction (MI) is the leading cause of mortality globally due in part to the limited ability of cardiomyocytes (CMs) to regenerate. Recently, we demonstrated that overexpression of four-cell cycle factors, CDK1, CDK4, cyclin B1 and cyclin D1 (4F), induced cell division in ~20% of the post-mitotic CMs overexpressed 4F. The current study aims to identify a small molecule that augments 4F-induced CM cycle induction. Screening of small molecules with a potential to augment 4F-induced cell-cycle induction in 60-day-old mature human induced pluripotent cardiomyocytes (hiPS-CMs) revealed N-(4,6-Dimethylpyridin-2-yl)-4-(pyridine-4-yl)piperazine-1-carbothioamide (NDPPC), which activates cell cycle progression in 4F-transduced hiPS-CMs. Autodock tool and Autodock vina computational methods showed that NDPPC has a potential interaction with the binding site at the human p38⍺ mitogen-activated protein kinase (p38⍺ MAP kinase), a critical negative regulator of the mammalian cell cycle. A p38 MAP kinase activity assay showed that NDPPC inhibits p38⍺ with 5-10 times lower IC compared to the other P38 isoforms in a dose-dependent manner. Overexpression of p38⍺ MAP kinase in CMs inhibited 4F cell cycle induction, and treatment with NDPPC reversed the cell cycle inhibitory effect. NDPPC is a novel inhibitor for p38 MAP kinase and is a promising drug to augment CM cell cycle response to the 4F. NDPPC could become an adjunct treatment with other cell cycle activators for heart failure treatment.