Recent Developments in Medicinal Chemistry and Therapeutic Potential of Anti-Cancer PROTACs-Based Molecules

Abstract

Background: PROTACs is an emerging technique that addresses the disease causing proteins by targeting protein degradation. PROTACs molecules are bifunctional small molecules that simultaneously bind to the protein of interest (POIs) and an E3 ligase followed by ubiquitination and degradation of the protein of interest by the proteasome.

Objective: PROTACs technology offers many advantages over classical inhibition such as PROTACs molecules can target intracellular proteins regardless of their function and have good tissue distribution. They are capable to target mutated and overexpressed proteins, thus potent molecules with the high degradation selectivity can be designed. Moreover, PROTACs molecules can target the undruggable proteome which makes up almost 85% of human proteins. Several PROTACs-based compounds have exhibited high therapeutic potency and some of them are currently under clinical trials.

Methods: Current article gives a comprehensive overview of the current development of PROTACs-based anticancer compounds along with the structure-activity relationship of the reported molecules.

Results: The development of PROTACs-based compounds and related research regarding medicinal chemistry is one of the most active and hot topics for research.

Conclusion: It is believed that the current review article can be helpful to understand the logical design of more efficacious PROTACs-based molecules with less toxicity and more selectivity.

Keywords: PROTACs; Targeted protein degradation; degradation; medicinal chemistry; structure activity relationship; ubiquitination.