Natural Product-Inspired Targeted Protein Degraders: Advances and Perspectives

Abstract

Targeted protein degradation (TPD), a promising therapeutic strategy in drug discovery, has great potential to regulate the endogenous degradation of undruggable targets with small molecules. As vital resources that provide diverse structural templates for drug discovery, natural products (NPs) are a rising and robust arsenal for the development of therapeutic TPD. The first proof-of-concept study of proteolysis-targeting chimeras (PROTACs) was a natural polyketide ovalicin-derived degrader; since then, NPs have shown great potential to promote TPD technology. The use of NP-inspired targeted protein degraders has been confirmed to be a promising strategy to treat many human conditions, including cancer, inflammation, and nonalcoholic fatty liver disease. Nevertheless, the development of NP-inspired degraders is challenging, and the field is currently in its infancy. In this review, we summarize the bioactivities and mechanisms of NP-inspired degraders and discuss the associated challenges and future opportunities in this field.

Drug discovery inspired by bioactive small molecules from nature

“…Wogonin-based PROTACs were also used for the synthesis of CDK9-targeting PROTACs capable of selectively degrading CDK9 (Bian et al 2018 ). Since the first study with PROTACs was performed with a natural polyketide ovalicin-derived molecule (Sakamoto et al 2001 ), the use of NP-mediated target protein degradation has emerged as a promising strategy to treat diseases such as cancer and metabolic disease (Li et al 2022 ).…”

PROTACs: A novel strategy for cancer drug discovery and development

“… 50,66–73 E3 ligases and the corresponding ligands are important as the driving force of protein degradation 74–91 . Good drug‐like small‐molecule ligands for a E3 ligase system are still limited 92–97 . Although more than 600 E3 ligases are encoded by human genome, only less than 10 E3 ligases were developed as ligands for the development of PROTAC degraders, including von Hippel‐Lindau (VHL), cereblon (CRBN), mouse double minute 2 (MDM2), cellular IAP1 (cIAP1), Kelch‐like ECH‐associated protein‐1 (KEAP1), DDB1‐cullin 4‐associated factor (DCAF), RING finger protein (RNF), aryl hydrocarbon receptor (AHR), and others (Figure 1).…”

Synthesis of Oleanolic Acid-Dithiocarbamate Conjugates and Evaluation of Their Broad-Spectrum Antitumor Activities

“…Natural products and their derivatives have a long history in cancer therapy and are important for drug development. Efficient and mild synthetic routes for bioactive natural product derivatives are of current interest for drug discovery [ 1 , 2 , 3 , 4 ]. Recently, pentacyclic triterpenes have been identified as the main biologically active components in many traditional Chinese medicines [ 5 , 6 ].…”