PROTACs: a novel strategy for cancer therapy

Publication date: Available online 11 February 2020Source: Seminars in Cancer BiologyAuthor(s): Jing Liu, Jia Ma, Yi Liu, Jun Xia, Yuyun Li, Z Peter Wang, Wenyi WeiAbstractChemotherapeutic 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-relevant fusion proteins such as NPM/EML4-ALK and BCL-ABL, cancer-driven mutant proteins such as EGFR, kinases such as CDKs and RTKs. The major disadvantage of PROTACs is the noncancer specificity and relative higher toxicity, due to its catalytic role. To overcome this, we and other have recently developed several similar lig...
Source: Seminars in Cancer Biology - Category: Cancer & Oncology Source Type: research