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Research ArticleCellular and Molecular

In vitro and in vivo anti-tumor and anti-inflammatory capabilities of the novel GSK3 and CKD9 inhibitor ABC1183.

Randy S Schrecengost, Cecelia L Green, Yan Zhuang, Staci N Keller, Ryan A Smith, Lynn W Maines and Charles D. Smith
Journal of Pharmacology and Experimental Therapeutics February 6, 2018, jpet.117.245738; DOI: https://doi.org/10.1124/jpet.117.245738
Randy S Schrecengost
Apogee Biotechnology Corporation
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Cecelia L Green
Apogee Biotechnology Corporation
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Yan Zhuang
Apogee Biotechnology Corporation
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Staci N Keller
Apogee Biotechnology Corporation
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Ryan A Smith
Apogee Biotechnology Corporation
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Lynn W Maines
Apogee Biotechnology Corporation
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Charles D. Smith
Apogee Biotechnology Corporation
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Abstract

Glycogen synthase kinase-3s (GSK3α and GSK3β) are constitutively active protein kinases that target over 100 substrates, incorporate into numerous protein complexes, and regulate vital cellular functions such 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, GS and β-catenin phosphorylation and MCL1 expression. Oral administration, which demonstrates no organ or hematological toxicity, suppresses tumor growth and inflammation-driven gastrointestinal disease symptoms, due in part to down regulation of TNFα and IL-6 pro-inflammatory cytokines. Therefore, ABC1183 is strategically poised to effectively mitigate multiple clinically relevant diseases.

  • anti-inflammatory drugs
  • anticancer agents
  • cancer
  • inflammatory bowel disease (IBD)
  • kinases
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 384 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 384, Issue 2
1 Feb 2023
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Research ArticleCellular and Molecular

In vitro and in vivo anti-tumor and anti-inflammatory capabilities of the novel GSK3 and CKD9 inhibitor ABC1183.

Randy S Schrecengost, Cecelia L Green, Yan Zhuang, Staci N Keller, Ryan A Smith, Lynn W Maines and Charles D. Smith
Journal of Pharmacology and Experimental Therapeutics February 6, 2018, jpet.117.245738; DOI: https://doi.org/10.1124/jpet.117.245738

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Research ArticleCellular and Molecular

In vitro and in vivo anti-tumor and anti-inflammatory capabilities of the novel GSK3 and CKD9 inhibitor ABC1183.

Randy S Schrecengost, Cecelia L Green, Yan Zhuang, Staci N Keller, Ryan A Smith, Lynn W Maines and Charles D. Smith
Journal of Pharmacology and Experimental Therapeutics February 6, 2018, jpet.117.245738; DOI: https://doi.org/10.1124/jpet.117.245738
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