In Vitro and In Vivo Antitumor and Anti-Inflammatory Capabilities of the Novel GSK3 and CDK9 Inhibitor ABC1183

Schrecengost, Randy S.; Green, Cecelia L.; Zhuang, Yan; Keller, Staci N.; Smith, Rhonda L.; Maines, Lynn W.; Smith, Charles D.

doi:10.1124/jpet.117.245738

Cited by 13 publications

(11 citation statements)

References 53 publications

(60 reference statements)

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“…ABC1183 had anti-tumor effects against multiple tumor types including melanoma and gastrointestinal tumors. ABC1183 also possessed anti-inflammatory effects against inflammatory bowel disease (IBM) [34].…”

Section: Gsk-3 Inhibitorsmentioning

confidence: 99%

Targeting GSK3 and Associated Signaling Pathways Involved in Cancer

Duda

Akula

Abrams

et al. 2020

Cells

177

132

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Glycogen synthase kinase 3 (GSK-3) is a serine/threonine (S/T) protein kinase. Although GSK-3 originally was identified to have functions in regulation of glycogen synthase, it was subsequently determined to have roles in multiple normal biochemical processes as well as various disease conditions. GSK-3 is sometimes referred to as a moonlighting protein due to the multiple substrates and processes which it controls. Frequently, when GSK-3 phosphorylates proteins, they are targeted for degradation. GSK-3 is often considered a component of the PI3K/PTEN/AKT/GSK-3/mTORC1 pathway as GSK-3 is frequently phosphorylated by AKT which regulates its inactivation. AKT is often active in human cancer and hence, GSK-3 is often inactivated. Moreover, GSK-3 also interacts with WNT/β-catenin signaling and β-catenin and other proteins in this pathway are targets of GSK-3. GSK-3 can modify NF-κB activity which is often expressed at high levels in cancer cells. Multiple pharmaceutical companies developed small molecule inhibitors to suppress GSK-3 activity. In addition, various natural products will modify GSK-3 activity. This review will focus on the effects of small molecule inhibitors and natural products on GSK-3 activity and provide examples where these compounds were effective in suppressing cancer growth.

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Section: Gsk-3 Inhibitorsmentioning

confidence: 99%

Targeting GSK3 and Associated Signaling Pathways Involved in Cancer

Duda

Akula

Abrams

et al. 2020

Cells

177

132

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“…yl]aminofuro[3,2-b]furylureas as a hit scaffold, it was decided to do a focussed SAR analysis on modifications of the hit structures. As a result, 20 further compounds(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41) were selected for Phase II in vitro binding assay experiments, that included a range of different substitutions at different positions (Figure8), including exploration of different furo[3,2b]furyl ring atom configurations for compounds 36-41. The GlideScores and predicted rankings of these ligands in the original in silico screening are included in Table…”

mentioning

confidence: 99%

Structure-Based Design of Potent Selective Nanomolar Type-II Inhibitors of Glycogen Synthase Kinase-3β

et al. 2021

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For the first time, the in silico design, screening and in vitro validation of potent GSK-3β type-II inhibitors is presented. In the absence of crystallographic evidence for DFGout GSK-3β activation loop conformation, computational models were designed using an adapted DOLPHIN approach and a method consisting of Prime loop refinement, induced-fit docking and molecular dynamics. Virtual screening of the Biogenics subset from the ZINC database led to an initial selection of 20 Phase I compounds revealing two low micromolar inhibitors in an isolated enzyme assay. 20 more analogues (Phase II compounds) related to the hit [pyrmidin-2-yl]amino-furo[3,2-b]furyl-urea scaffold were selected for structure activity relationship analysis. The Phase II studies lead to five highly potent nanomolar inhibitors, with compound 23 (IC50 =0.087 µM) >100 times more potent than the best Phase I inhibitor, and selectivity for GSK-3β inhibition compared to homologous kinases observed. Ex-vivo experiments (SH-SY5Y cell lines) for tau hyperphosphorylation revealed promising neuroprotective effects at low micromolar concentrations. Type-II inhibitor design has been unraveled as a potential route towards more clinically effective GSK-3β inhibitors.

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“…Other relevant target hits of AF included GSK3A, GSK3B, MCMBP and EEFSEC ( Supplementary Table 3 ). Both GSK3 proteins affect a multitude of cellular pathways, including glycogen synthesis, WNT signaling and inflammation [ 60 ]: e.g., GSK3 inhibitors have anti-inflammatory properties [ 61 ]. Thus, AF anti-inflammatory properties might originate at least in part from the inhibition of GSK3A and GSK3B.…”

Section: Resultsmentioning

confidence: 99%