Refine
Departments, institutes and facilities
Document Type
- Article (56)
- Conference Object (6)
- Part of a Book (2)
- Contribution to a Periodical (1)
- Patent (1)
- Working Paper (1)
Year of publication
Keywords
- Force field (3)
- Software (2)
- ACPYPE (1)
- AMBER (1)
- AML (1)
- Alkane (1)
- Atomistic force fields (1)
- Basis set (1)
- Binding Sites (1)
- Carbohydrate (1)
Mebendazole Mediates Proteasomal Degradation of GLI Transcription Factors in Acute Myeloid Leukemia
(2021)
The prognosis of elderly AML patients is still poor due to chemotherapy resistance. The Hedgehog (HH) pathway is important for leukemic transformation because of aberrant activation of GLI transcription factors. MBZ is a well-tolerated anthelmintic that exhibits strong antitumor effects. Herein, we show that MBZ induced strong, dose-dependent anti-leukemic effects on AML cells, including the sensitization of AML cells to chemotherapy with cytarabine. MBZ strongly reduced intracellular protein levels of GLI1/GLI2 transcription factors. Consequently, MBZ reduced the GLI promoter activity as observed in luciferase-based reporter assays in AML cell lines. Further analysis revealed that MBZ mediates its anti-leukemic effects by promoting the proteasomal degradation of GLI transcription factors via inhibition of HSP70/90 chaperone activity. Extensive molecular dynamics simulations were performed on the MBZ-HSP90 complex, showing a stable binding interaction at the ATP binding site. Importantly, two patients with refractory AML were treated with MBZ in an off-label setting and MBZ effectively reduced the GLI signaling activity in a modified plasma inhibitory assay, resulting in a decrease in peripheral blood blast counts in one patient. Our data prove that MBZ is an effective GLI inhibitor that should be evaluated in combination to conventional chemotherapy in the clinical setting.
Quantum mechanical theories are used to search and optimized the conformations of proposed small molecule candidates for treatment of SARS-CoV-2. These candidate compounds are taken from what is reported in the news and in other pre-peer-reviewed literature (e.g. ChemRxiv, bioRxiv). The goal herein is to provided predicted structures and relative conformational stabilities for selected drug and ligand candidates, in the hopes that other research groups can make use of them for developing a treatment.