Protac Technology in Cancer Drug Developmentâ...

Protac Technology in Cancer Drug Development– A Review

Author Name : Helina N, Ramalakshmi Natarajan, Yuvarani K, Amuthalakshmi S

ABSTRACT

Majority of currently used therapeutics in cancer are small molecule-based and monoclonal antibodies, in which the protein function is modulated via temporary inhibition. One of the major pathways to modulate the protein function is Ubiquitin Proteasome system. Proteolysis Targeting Chimera (PROTAC) technology is a promising therapy which achieve protein degradation through Ubiquitin Proteasome pathway thereby it overcomes the shortages of small molecule inhibitor and antibodies for cancer therapy. PROTACs are hetero bifunctional molecules that recruit an E3 ubiquitin ligase to a target protein and induce a degradation of target protein. In this review we discussed the first generation peptide based PROTACs , but due to poor cell permeability, high molecular weight, low potency of peptide moieties limited its use. This drawbacks are bypassed by small molecule PROTACs have been widely studied. Mutation or over expression or abnormal regulations of ubiquitin ligase have been identified in cancer. By approaching PROTAC technology numerous targets were successfully undergoes protein degradation. We focused on the targets of PROTACs including those over expressed oncogenic proteins such as Androgen receptor, Estrogen Receptor, B-Cell lymphoma-2, Bruton’s Tyrosine Kinase, Indoleamine 2, 3 deoxygenase-I, Bromo and Extra terminal domain proteins are discussed.

Keywords: E3 ubiquitin ligase, Proteasome, Cancer therapy, Oncogenic Proteins