STRUCTURAL MODIFICATION OF THE PROPYL LINKER OF CJOC42 FOR ENHANCED GANKYRIN BINDING AND ANTI-CANCER ACTIVITY

Gankyrin was first identified as an oncoprotein in hepatocellular carcinoma but was later found to be overexpressed in multiple cancer types. Gankyrin’s oncogenic ability is primarily manifested through its interactions with tumor suppressor proteins, regulation of transcription factors, and ability to moderate various signaling pathways. Additionally, gankyrin has been shown to decrease tumor suppressor protein levels (e.g., Rb and p53) in liver cancer cells. Cjoc42 was the first small molecule inhibitor of gakyrin; however, it also demonstrated poor anti-proliferative activity against liver cancer cells. Molecular modeling studies of cjoc42 with gankyrin suggests cjoc42 adopts a U-shape conformation upon binding to gankyrin, which may be contribute for its activity. To assess the importance of this U-shape conformation on anti-proliferative activity and gankyrin binding ability, the propyl linker of the cjovc42 scaffold was replaced with various cyclic and acyclic linkers. These derivatives helped in understanding the impact of cjoc42 conformational flexibility and rigidity on the anti-proliferative activity and gankyrin binding in liver and breast cancer cells. Conformationally constrained derivatives then significantly improved the anti-proliferative activity against HuH6 and MDA-MB-231 cells while also showing an ability to effectively bind gankyrin, disrupt the proteasomal degradation pathway, and cause cell cycle arrest

Repurposing Bedaquiline for Effective Non-Small Cell Lung Cancer (NSCLC) Therapy as Inhalable Cyclodextrin-Based Molecular Inclusion Complexes

There is growing evidence that repurposed drugs demonstrate excellent efficacy against many cancers, while facilitating accelerated drug development process. In this study, bedaquiline (BDQ), an FDA approved anti-mycobacterial agent, was repurposed and an inhalable cyclodextrin complex formulation was developed to explore its anti-cancer activity in non-small cell lung cancer (NSCLC). A sulfobutyl ether derivative of β-cyclodextrin (SBE-β-CD) was selected based on phase solubility studies and molecular modeling to prepare an inclusion complex of BDQ and cyclodextrin. Aqueous solubility of BDQ was increased by 2.8 × 103-fold after complexation with SBE-β-CD, as compared to its intrinsic solubility. Solid-state characterization studies confirmed the successful incorporation of BDQ in the SBE-β-CD cavity. In vitro lung deposition study results demonstrated excellent inhalable properties (mass median aerodynamic diameter: 2.9 ± 0.6 µm (<5 µm) and fine particle fraction: 83.3 ± 3.8%) of BDQ-CD complex. Accelerated stability studies showed BDQ-CD complex to be stable up to 3 weeks. From cytotoxicity studies, a slight enhancement in the anti-cancer efficacy was observed with BDQ-cyclodextrin complex, compared to BDQ alone in H1299 cell line. The IC50 values for BDQ and BDQ-CD complex were found to be ~40 µM in case of H1299 cell line at 72 h, whereas BDQ/BDQ-CD were not found to be cytotoxic up to concentrations of 50 µM in A549 cell line. Taken together, BDQ-CD complex offers a promising inhalation strategy with efficient lung deposition and cytotoxicity for NSCLC treatment

Synthesis and evaluation of 2,5-substituted pyrimidines as small-molecule gankyrin binders

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