RESUMEN
This study reported the design and synthesis of novel 1-amido-2-one-4-thio-deoxypyranose as inhibitors of potential drug target TRIP13 for developing new mechanism-based therapeutic agents in the treatment of multiple myeloma (MM). In comparison with the positive control DCZ0415, the most active compounds C16, C18, C20 and C32 exhibited strong anti-proliferative activity against human MM cell lines (ARP-1 and NCI-H929) with IC50 values of 1 â¼ 2 µM. While the surface plasmon resonance (SPR) and ATPase activity assays demonstrated that the representative compound C20 is a potent inhibitor of TRIP13, C20 also showed good antitumor activity in vivo on BALB/c nude mice xenografted with MM tumor cells. An initial structure-activity study showed that the carbonyl group is crucial for anticancer activity. Overall, this study provided novel 1-amido-2-one-4-thio-deoxypyranoses, which are entirely different from previously reported potent inhibitor structures of TRIP13, and thus would aid the development of carbohydrate-based novel agents in MM pharmacotherapy.
RESUMEN
ATPases Associated with Diverse Cellular Activity (AAA+ATPases) are important enzymatic functional proteins in human cells. Thyroid Hormone Receptor Interacting Protein-13 (TRIP13) is a member of this protein superfamily, that partly regulates DNA repair pathways and spindle assembly checkpoints during mitosis. TRIP13 is reported as an oncogene involving multiple pathways in many human malignancies, including multiple myeloma, brain tumors, etc. The structure of TRIP13 reveals the mechanisms for ATP binding and how TRIP13 recognizes the Mitotic Arrest Deficiency-2 (MAD2) protein, with p31comet acting as an adapter protein. DCZ0415, TI17, DCZ5417, and DCZ5418 are the reported small-molecule inhibitors of TRIP13, which have been demonstrated to inhibit TRIP13's biological functions significantly and effective in suppressing various types of malignant cells, indicating that TRIP13 is a significant anticancer drug target. Currently, no systematic reviews are cutting across the functions, structure, and novel inhibitors of TRIP13. This review provides a comprehensive overview of TRIP13's biological functions, its roles in eighteen different cancers, four small molecule inhibitors, different underlying molecular mechanisms, and its functionality as a potential anticancer drug target.
RESUMEN
The coronavirus disease 2019 (COVID-19) pandemic is an ongoing global health concern, and effective antiviral reagents are urgently needed. Traditional Chinese medicine theory-driven natural drug research and development (TCMT-NDRD) is a feasible method to address this issue as the traditional Chinese medicine formulae have been shown effective in the treatment of COVID-19. Huashi Baidu decoction (Q-14) is a clinically approved formula for COVID-19 therapy with antiviral and anti-inflammatory effects. Here, an integrative pharmacological strategy was applied to identify the antiviral and anti-inflammatory bioactive compounds from Q-14. Overall, a total of 343 chemical compounds were initially characterized, and 60 prototype compounds in Q-14 were subsequently traced in plasma using ultrahigh-performance liquid chromatography with quadrupole time-of-flight mass spectrometry. Among the 60 compounds, six compounds (magnolol, glycyrrhisoflavone, licoisoflavone A, emodin, echinatin, and quercetin) were identified showing a dose-dependent inhibition effect on the SARS-CoV-2 infection, including two inhibitors (echinatin and quercetin) of the main protease (Mpro), as well as two inhibitors (glycyrrhisoflavone and licoisoflavone A) of the RNA-dependent RNA polymerase (RdRp). Meanwhile, three anti-inflammatory components, including licochalcone B, echinatin, and glycyrrhisoflavone, were identified in a SARS-CoV-2-infected inflammatory cell model. In addition, glycyrrhisoflavone and licoisoflavone A also displayed strong inhibitory activities against cAMP-specific 3',5'-cyclic phosphodiesterase 4 (PDE4). Crystal structures of PDE4 in complex with glycyrrhisoflavone or licoisoflavone A were determined at resolutions of 1.54 Å and 1.65 Å, respectively, and both compounds bind in the active site of PDE4 with similar interactions. These findings will greatly stimulate the study of TCMT-NDRD against COVID-19.