In Vitro and In Vivo Antitumor and Anti-Inflammatory Capabilities of the Novel GSK3 and CDK9 Inhibitor ABC1183

• Published in: The Journal of pharmacology and experimental therapeutics 2018-04, Vol.365 (1), p.107-116
• Main Authors: Schrecengost, Randy S, Green, Cecelia L, Zhuang, Yan, Keller, Staci N, Smith, Ryan A, Maines, Lynn W, Smith, Charles D
• Format: Article
• Language: English
• Subjects: Cellular and Molecular
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.117.245738

Glycogen synthase kinase-3s (GSK3 and GSK3 ) 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 GSK3 / 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 -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 and interleukin-6 proinflammatory cytokines. Therefore, ABC1183 is strategically poised to effectively mitigate multiple clinically relevant diseases.