PT - JOURNAL ARTICLE AU - Randy S Schrecengost AU - Cecelia L Green AU - Yan Zhuang AU - Staci N Keller AU - Ryan A Smith AU - Lynn W Maines AU - Charles D. Smith TI - In vitro and in vivo anti-tumor and anti-inflammatory capabilities of the novel GSK3 and CKD9 inhibitor ABC1183. AID - 10.1124/jpet.117.245738 DP - 2018 Jan 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - jpet.117.245738 4099 - http://jpet.aspetjournals.org/content/early/2018/02/06/jpet.117.245738.short 4100 - http://jpet.aspetjournals.org/content/early/2018/02/06/jpet.117.245738.full 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 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.