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Research ArticleCellular and Molecular

In Vitro and In Vivo Antitumor and Anti-Inflammatory Capabilities of the Novel GSK3 and CDK9 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 April 2018, 365 (1) 107-116; DOI: https://doi.org/10.1124/jpet.117.245738
Randy S. Schrecengost
Apogee Biotechnology Corporation, Hummelstown, Pennsylvania
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Cecelia L. Green
Apogee Biotechnology Corporation, Hummelstown, Pennsylvania
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Yan Zhuang
Apogee Biotechnology Corporation, Hummelstown, Pennsylvania
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Staci N. Keller
Apogee Biotechnology Corporation, Hummelstown, Pennsylvania
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Ryan A. Smith
Apogee Biotechnology Corporation, Hummelstown, Pennsylvania
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Lynn W. Maines
Apogee Biotechnology Corporation, Hummelstown, Pennsylvania
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Charles D. Smith
Apogee Biotechnology Corporation, Hummelstown, Pennsylvania
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    Fig. 1.

    ABC1183 selectively inhibits GSK3 α/β and CDK9. (A) Structure of ABC1183. (B) Top, in vitro kinase screen with 10 μM ABC1183 and graphical representation of inhibition. Bottom, four kinases with inhibition >60%. (C) Dose-response assay calculating IC50 values of GSK3α, GSK3β, and CDK9.

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    Fig. 2.

    ABC1183 exhibits cytotoxicity against a panel of murine and human cancer cells. (A) The indicated cell lines were seeded into 96-well plates at determined subconfluent concentrations and 24 hours later were treated with a dose response of ABC1183 for 72 hours. Cell survival was quantified by sulforhodamine B assay. IC50 value for each cell line shown. (B) Pan02 cells were treated with dimethyl sulfoxide (DMSO) or 3 μM ABC1183 for 24 hours and cell cycle was analyzed by propidium iodide staining. Representative histogram plots are shown.

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    Fig. 3.

    Multiple tumorigenic signaling pathways are inhibited by ABC1183. (A) LNCaP, (B) Pan02, (C) FaDu cells were treated with 3 μM ABC1183 for 2–24 hours or 20 nM LY2090314, as indicated. Cell lysates were immunoblotted with MCL1, pSer21/9 GSK3α/β, GSK3β, pSer641 GS, GS, pSer33/37 Thr41 β-catenin, β-catenin, and GAPDH.

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    Fig. 4.

    Inhibition of tumor growth by ABC1183. C57BL/6 mice were injected subcutaneously with (A) B16 melanoma cells suspended in PBS, (B) PAN02 pancreatic cancer cells suspended in PBS/growth matrix, or (C) TRAMP-C2 murine prostate cancer cells suspended in PBS/growth matrix. After tumor volume of at least 100 mm3, animals were treated five times per week by oral gavage of either 100 μl vehicle (open squares), 5 mg/kg ABC1183 (A and B), or 2 mg/kg ABC1183 (C) (gray squares). Tumor volume measurement was performed for time course as indicated; n = 5 per group in (A) and (C), n = 10 per group for (B). *P < 0.05; **P < 0.01. (D) Pan02-bearing mice were treated with 5 or 25 mg/kg for 2 or 12 hours. Tumors were excised, snap frozen, processed, and tumor lysates immunoblotted with pSer21/9 GSK3α/β, GSK3β, pSer641 GS, and GS.

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    Fig. 5.

    ABC1183 is safe for oral administration and reduces severity of TNBS-colitis model, at least in part, through inflammatory cytokines. (A) Seven-day toxicity of ABC1183. The indicated dose of ABC1183 was administered by oral gavage daily for 7 days, and the mice were then sacrificed for hematology, blood chemistry, and organ weight analyses. Values are mean ± S.E.M., n = 3 or 4 mice/group. (B) C57BL/6 mice were treated with rectal 50% ethanol and oral vehicle (black bars); rectal TNBS and oral vehicle (cross hatched bars), or rectal TNBS or oral ABC1183 (gray bars 50 mg/kg). Animals were sacrificed on day 10 and macroscopic inflammation within the distal 3 cm of each colon was scored. (C) Mice were treated as in (B) and TNF-α and IL-6 cytokines levels were determined from colon samples. *P < 0.05; **P < 0.01.

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    Fig. 6.

    Effect of oral ABC1183 on disease parameters in the mouse DSS-induced ulcerative colitis. C57BL/6 mice were treated with oral vehicle (black bars), 2% DSS-positive control (horizontal hatched bars), or 2% DSS with oral ABC1183 50 mg/kg twice a day (gray bars), and the following parameters were measured: (A) Disease Activity Index (DAI), which monitors disease severity; (B) colon length on day 6 of treatment; (C) myeloperoxidase (MPO) activity measured from the colons of animals on day 6 of treatment. (D) Cytokine values: TNFα, IL-6, and IL-10 cytokine levels were determined from colon samples. *P < 0.05; **P < 0.01.

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Journal of Pharmacology and Experimental Therapeutics: 365 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 365, Issue 1
1 Apr 2018
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Research ArticleCellular and Molecular

Dual Targeting GSK3 and CDK9 with Novel 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 April 1, 2018, 365 (1) 107-116; DOI: https://doi.org/10.1124/jpet.117.245738

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Research ArticleCellular and Molecular

Dual Targeting GSK3 and CDK9 with Novel 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 April 1, 2018, 365 (1) 107-116; DOI: https://doi.org/10.1124/jpet.117.245738
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