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Updated: Sep 6, 2025
Author Spotlight: Evaluating Biophysical Assays for Characterizing PROTACS Ternary Complexes
Published on: January 12, 2024
Developing PROteolysis TArgeting Chimeras (PROTACs) for hematologic malignancies
Yangping Wu1, Jingliao Zhang1, Xiaofan Zhu1
1Division of Pediatric Blood Diseases Center, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China; State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China.
Abstract:
PROteolysis TArgeting Chimeras (PROTACs) degrade target proteins via the ubiquitin-proteasome system, providing novel insights into drug development for hematologic malignancies. PROTACs outperform conventional therapeutics and currently available small molecule inhibitors in terms of efficacy, tissue-and cell-selectivity, and side effect profile. Most importantly, PROTACs are a powerful tool for addressing "undruggable" oncogenic proteins. Despite their numerous benefits, PROTACs as therapeutics face many challenges not only in the design and synthesis but also in the evaluation of anticancer effects and clinical application. In this article, we focus on PROTACs that have demonstrated preclinical efficacy and clinical potential in the treatment of various hematologic malignancies in the last 5 years. We start with a brief overview of the functioning mechanism and major breakthroughs in this field. To provide a balanced perspective on PROTACs, we discuss the pros and cons of exploiting PROTACs for therapeutic purposes. Following that, we brainstorm ideas to optimize PROTACs for clinical application. More PROTACs will enter clinical trials soon, benefiting patients with hematologic malignancies.
Insights
PROteolysis TArgeting Chimeras (PROTACs) offer a novel therapeutic approach for hematologic malignancies by degrading target proteins. PROTACs show promise for treating "undruggable" cancers, despite design and clinical challenges.
Area of Science:
- Biochemistry
- Oncology
- Drug Discovery
Background:
- PROteolysis TArgeting Chimeras (PROTACs) leverage the ubiquitin-proteasome system for targeted protein degradation.
- PROTACs present a significant advancement over traditional therapeutics for hematologic malignancies.
- They offer enhanced efficacy, selectivity, and improved side effect profiles.
Purpose of the Study:
- To review PROTACs with demonstrated preclinical and clinical potential in hematologic malignancies over the past five years.
- To provide an overview of PROTACs' mechanism of action and recent breakthroughs.
- To discuss the advantages and disadvantages of PROTACs in therapeutic applications.
Main Methods:
- Literature review focusing on PROTACs in hematologic malignancies.
- Analysis of preclinical efficacy and clinical trial data.
- Discussion of design, synthesis, and evaluation challenges.
Main Results:
- PROTACs show significant promise in degrading oncogenic proteins, including previously
- undruggable
- targets.
- Recent studies highlight PROTACs' efficacy and selectivity in preclinical models of hematologic cancers.
- Several PROTACs are advancing toward or are in clinical trials for these indications.
Conclusions:
- PROTACs represent a powerful therapeutic strategy for hematologic malignancies, addressing unmet needs.
- Optimization of PROTACs is crucial for overcoming current challenges in clinical application.
- Continued development and clinical trials are expected to benefit patients with hematologic malignancies.
