Folate-Guided Protein Degradation by Immunomodulatory Imide Drug-Based Molecular Glues and Proteolysis Targeting Chimeras

Molecular glues and proteolysis targeting chimeras (PROTACs) are promising new therapeutic modalities. However, the lack of specificity for molecular glue- or PROTAC-mediated proteolysis in cancer cells versus normal cells raises potential toxicity concerns that will likely limit their clinical applications. Here, we developed a general strategy to deliver immunomodulatory imide drug (IMiD)-based molecular glues and PROTACs to folate receptor α (FOLR1)-positive cancer cells. Specifically, we designed a folate-caged pomalidomide prodrug, FA-S2-POMA, by incorporating a folate group as a caging and guiding element and validated its degradation effect on its neo-substrates in FOLR1-positive cancer cells in a FOLR1-dependent manner. We also developed a folate-caged pomalidomide-based anaplastic lymphoma kinase (ALK) PROTAC, FA-S2-MS4048, which effectively degraded ALK fusion proteins in cancer cells, again in a FOLR1-dependent manner. This novel approach provides a generalizable platform fo..... READ ARTICLE

Journal of Medicinal Chemistry DOI:10.1021/acs.jmedchem.1c00901

Authors: He Chen, Jing Liu, H. Ümit Kaniskan, Wenyi Wei, and Jian Jin

Pre-ClinicalKirk SmithAugust 11, 2021Nutrition, High-performance liquid chromatography, Mixtures, Cells, Organic compounds, PROTACs

PROTACs: A novel strategy for cancer therapy

Chemotherapeutic strategy has been widely used for treating malignance by targeting irregular expressed or mutant proteins with small molecular inhibitors (SMIs) or monoclonal antibodies (mAbs). However, most intracellular proteins lack of active sites or antigens where SMIs or mAbs bind with, and are called as non-druggable targets for a long time. From the first year of this century, PROteolysis-TArgeting Chimeras (PROTACs) has emerged to be a promising approach for proteins, including those non-druggable ones, such as transcriptional factors and scaffold proteins. The first generation of peptide-based PROTACs adopts β-TrCP and VHL as E3 ligases, but the cellular permeability and chemical stability issues restrict their clinical application. The second generation of small molecule-based PROTACs adopts MDM2, VHL, IAPs and Cereblon as E3 ligases have been tensely studied. To date, the targets of PROTACs including those overexpressed oncogenic proteins such as ER, AR and BRDs, disease-r..... READ ARTICLE

Seminars in Cancer Biology DOI:10.1016/j.semcancer.2020.02.006

Authors: Jing Liu, Jia Ma, Yi Liua, Jun Xia, Yuyun Li, Z. Peter Wang, Wenyi Wei

Conference PaperKirk SmithDecember 1, 2020PROTACs, Cancer, Therapyopto-PROTAC, pcPROTAC, PHOTAC, Photo-PROTAC