In Vitro and In Vivo Antitumor and Anti-Inflammatory Capabilities of the Novel GSK3 and CDK9 Inhibitor ABC1183
| Autor: | Randy S. Schrecengost, Ryan A. Smith, Staci N. Keller, Cecelia L. Green, Charles D. Smith, Lynn W. Maines, Yan Zhuang |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
Cellular and Molecular
0301 basic medicine Anti-Inflammatory Agents Antineoplastic Agents Proinflammatory cytokine Glycogen Synthase Kinase 3 03 medical and health sciences 0302 clinical medicine Downregulation and upregulation Nitriles Humans MCL1 P-TEFb Glycogen synthase Protein Kinase Inhibitors Pharmacology biology Kinase Chemistry Inflammatory Bowel Diseases Cyclin-Dependent Kinase 9 030104 developmental biology 030220 oncology & carcinogenesis biology.protein Cancer research Molecular Medicine Phosphorylation Cyclin-dependent kinase 9 |
| Zdroj: | Journal of Pharmacology and Experimental Therapeutics. 365:107-116 |
| ISSN: | 1521-0103 0022-3565 |
| Popis: | Glycogen synthase kinase-3s (GSK3α and GSK3β) are constitutively active protein kinases that target over 100 substrates, incorporate into numerous protein complexes, and regulate such vital cellular functions as proliferation, apoptosis, and inflammation. Cyclin-dependent kinase 9 (CDK9) regulates RNA production as a component of positive transcription elongation factor b and promotes expression of oncogenic and inflammatory genes. Simultaneous inhibition of these signaling nodes is a promising approach for drug discovery, although previous compounds exhibit limited selectivity and clinical efficacy. The novel diaminothiazole ABC1183 is a selective GSK3α/β and CDK9 inhibitor and is growth-inhibitory against a broad panel of cancer cell lines. ABC1183 treatment decreases cell survival through G2/M arrest and modulates oncogenic signaling through changes in GSK3, glycogen synthase, and β-catenin phosphorylation and MCL1 expression. Oral administration, which demonstrates no organ or hematologic toxicity, suppresses tumor growth and inflammation-driven gastrointestinal disease symptoms, owing in part to downregulation of tumor necrosis factor α and interleukin-6 proinflammatory cytokines. Therefore, ABC1183 is strategically poised to effectively mitigate multiple clinically relevant diseases. |
| Databáze: | OpenAIRE |
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