Trans-(±)-TTPG-B Attenuates Cell Cycle Progression and Inhibits Cell Proliferation on Cholangiocarcinoma Cells.

Abstract

This research aimed to determine the target protein and molecular mechanism of trans-(±)-kusunokinin ((±)-KU) derivatives (trans-(±)-ARC and trans-(±)-TTPG-B). Molecular docking was used to predict potential synthesized (±)-KU targets among 22 proteins. The (±)-TTPG-B bound HSP90α better than EC44, native (±)-KU and (-)-KU, and (±)-KU and (-)-ARC. In contrast, (-)-ARC bound PI3K more strongly than any other test compound. CSF1R and AKR1B1 were not supposed to be the target of (±)-TTPG-B and (±)-ARC, unlike native (±)-KU. The (±)-TTPG-B bound Tyr139 and Trp162 of HSP90α. Moreover, (-)-ARC bound PI3K via hydrogen bonds and π-π stacking at distinct amino acids, which was different from the other tested compounds. Using half of the IC50 concentration, (±)-TTPG-B, (±)-KU and (±)-ARC enhanced cell cycle arrest at the G0/G1 phase after 12 h and 24 h on KKU-M213 (CCA) cells. The (±)-TTPG-B showed a stronger inhibitory effect than (±)-ARC and (±)-KU on HSP90α, PI3K, HSP90β, c-Myc, AKT, MEK1, CyclinB1, CyclinD1, and CDK1 for 24 and 48 h after treatment with the same concentration (0.015 µM). Thus, trans-(±)-TTPG-B, a newly synthesized compound, has pharmacological potential for development as a target therapy for CCA treatment.

• Authors: Thidarath Rattanaburee, Chompunud Chompunud Na Ayudhya, Tienthong Thongpanchang, Varomyalin Tipmanee, Potchanapond Graidist
• Journal: Molecules (Basel, Switzerland) (Molecules) Vol. 28 Issue 21 (Oct 30 2023) ISSN: 1420-3049 [Electronic] Switzerland
• PMID: 37959760 (Publication Type: Journal Article)

Chemical References

• stepronin
• Phosphatidylinositol 3-Kinases
• AKR1B1 protein, human
• Aldehyde Reductase

Topics

• Humans
• Molecular Docking Simulation
• Cholangiocarcinoma (pathology)
• Cell Proliferation
• Cell Division
• Bile Ducts, Intrahepatic (metabolism, pathology)
• Bile Duct Neoplasms (pathology)
• Phosphatidylinositol 3-Kinases
• Cell Line, Tumor
• Apoptosis
• Cell Cycle
• Aldehyde Reductase