Proteolysis targeting chimeras (PROTACs) are emerging therapeutics for hematologic malignancies

Yonghan He,Zhiguang Huo,Dongwen Lv,Mingjiang Xu,Daohong Zhou,Sajid Khan,Yaxia Yuan,Guangrong Zheng,Xingui Liu,Xuan Zhang,Robert Hromas

doi:10.1186/s13045-020-00924-z

Abstract

Proteolysis targeting chimeras (PROTACs) are heterobifunctional small molecules that utilize the ubiquitin proteasome system (UPS) to degrade proteins of interest (POI). PROTACs are potentially superior to conventional small molecule inhibitors (SMIs) because of their unique mechanism of action (MOA, i.e., degrading POI in a sub-stoichiometric manner), ability to target “undruggable” and mutant proteins, and improved target selectivity. Therefore, PROTACs have become an emerging technology for the development of novel targeted anticancer therapeutics. In fact, some of these reported PROTACs exhibit unprecedented efficacy and specificity in degrading various oncogenic proteins and have advanced to various stages of preclinical and clinical development for the treatment of cancer and hematologic malignancy. In this review, we systematically summarize the known PROTACs that have the potential to be used to treat various hematologic malignancies and discuss strategies to improve the safety of PROTACs for clinical application. Particularly, we propose to use the latest human pan-tissue single-cell RNA sequencing data to identify hematopoietic cell type-specific/selective E3 ligases to generate tumor-specific/selective PROTACs. These PROTACs have the potential to become safer therapeutics for hematologic malignancies because they can overcome some of the on-target toxicities of SMIs and PROTACs.

Highlights

Proteolysis targeting chimeras (PROTACs) are bivalent small molecules consisting of a ligand that binds to a protein of interest (POI) connected via a linker to a recruitment moiety for an E3 ubiquitin ligase [1]
PROTACs act catalytically to induce protein degradation in a substoichiometric manner [1]. Because of this unique mechanism of action (MOA), PROTACs produce longer and stronger biological effects than small molecule inhibitors (SMIs) on a target, which allow PROTACs to be used at a much less intensive dosing regimen to be therapeutically effective than SMIs and reduce the risk of undesirable side effects that usually result from off-target binding of SMIs when used at higher concentrations
Conclusions and perspectives of PROTACs as therapeutics for hematologic malignancies Targeted protein degradation using PROTACs has emerged as a novel therapeutic modality in drug discovery

Summary

Introduction

Proteolysis targeting chimeras (PROTACs) are bivalent small molecules consisting of a ligand that binds to a protein of interest (POI) connected via a linker to a recruitment moiety for an E3 ubiquitin ligase [1]. Another VHL-based ALK PROTAC TD-004 efficiently induced ALK degradation and inhibited the proliferation of SUDHL-1 and H3122 cells in vitro, and reduced H3122 xenografted tumor growth in vivo [41]. DT2216, a representative PROTAC that hijacks the VHL E3 ligase to achieve tissue/cell-selective degradation of Bcl-xL, was found to be more potent against Bcl-xL-dependent tumor cells and less toxic against platelets in comparison to conventional Bcl-xL inhibitors.

Results

Conclusion