In vitro and in vivo antitumor and anti-inflammatory capabilities of the novel GSK3 and CDK9 inhibitor ABC1183s

Randy S. Schrecengost, Cecelia L. Green, Yan Zhuang, Staci N. Keller, Ryan A. Smith, Lynn W. Maines, Charles Smith

Research output: Contribution to journalArticle

2 Scopus citations

Abstract

Glycogen synthase kinase-3s (GSK3a and GSK3b) are consti-tutively 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 GSK3a/b 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 b-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 a and interleukin-6 proinflammatory cytokines. Therefore, ABC1183 is strategically poised to effectively mitigate multiple clinically relevant diseases.

Original languageEnglish (US)
Pages (from-to)107-116
Number of pages10
JournalJournal of Pharmacology and Experimental Therapeutics
Volume365
Issue number1
DOIs
StatePublished - Apr 1 2018

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Pharmacology

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