The research presented here not only describes attempts to develop selective inhibitors for SENPs and PARK7 but also provides a chemical toolbox to study the function of PARK7. Both SENPs and PARK7... Show moreThe research presented here not only describes attempts to develop selective inhibitors for SENPs and PARK7 but also provides a chemical toolbox to study the function of PARK7. Both SENPs and PARK7 are attractive therapeutic targets for drug development. The results of the research and chemical tools described in this thesis will further aid in the development of more potent and selective inhibitors of SENPs and PARK7 for therapeutic purposes. Show less
Merbel, A.F. van de; Hooij, O. van; Horst, G. van der; Rijt-van de Westerlo, C.C.M. van; Mark, M.H. van der; Cheung, H.; ... ; Pluijm, G. van der 2021
Transformed epithelial cells can activate programs of epithelial plasticity and switch from a sessile, epithelial phenotype to a motile, mesenchymal phenotype. This process is linked to the... Show moreTransformed epithelial cells can activate programs of epithelial plasticity and switch from a sessile, epithelial phenotype to a motile, mesenchymal phenotype. This process is linked to the acquisition of an invasive phenotype and the formation of distant metastases. The development of compounds that block the acquisition of an invasive phenotype or revert the invasive mesenchymal phenotype into a more differentiated epithelial phenotype represent a promising anticancer strategy. In a high-throughput assay based on E-cadherin (re)induction and the inhibition of tumor cell invasion, 44,475 low molecular weight (LMW) compounds were screened. The screening resulted in the identification of candidate compounds from the PROAM02 class. Selected LMW compounds activated E-cadherin promoter activity and inhibited cancer cell invasion in multiple metastatic human cancer cell lines. The intraperitoneal administration of selected LMW compounds reduced the tumor burden in human prostate and breast cancer in vivo mouse models. Moreover, selected LMW compounds decreased the intra-bone growth of xenografted human prostate cancer cells. This study describes the identification of the PROAM02 class of small molecules that can be exploited to reduce cancer cell invasion and metastases. Further clinical evaluation of selected candidate inhibitors is warranted to address their safety, bioavailability and antitumor efficacy in the management of patients with aggressive cancers. Show less
