RT Journal Article
SR Electronic
T1 In Vitro and In Vivo Antitumor and Anti-Inflammatory Capabilities of the Novel GSK3 and CDK9 Inhibitor ABC1183
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 107
OP 116
DO 10.1124/jpet.117.245738
VO 365
IS 1
A1 Schrecengost, Randy S.
A1 Green, Cecelia L.
A1 Zhuang, Yan
A1 Keller, Staci N.
A1 Smith, Ryan A.
A1 Maines, Lynn W.
A1 Smith, Charles D.
YR 2018
UL http://jpet.aspetjournals.org/content/365/1/107.abstract
AB 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.