TY - JOUR
T1 - Proteolysis targeting chimeras (PROTACs) are emerging therapeutics for hematologic malignancies
AU - He, Yonghan
AU - Khan, Sajid
AU - Huo, Zhiguang
AU - Lv, Dongwen
AU - Zhang, Xuan
AU - Liu, Xingui
AU - Yuan, Yaxia
AU - Hromas, Robert
AU - Xu, Mingjiang
AU - Zheng, Guangrong
AU - Zhou, Daohong
N1 - Publisher Copyright:
© 2020 The Author(s).
PY - 2020/7/27
Y1 - 2020/7/27
N2 - 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.
AB - 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.
KW - Cell-specific E3 ligases
KW - Hematologic malignancy
KW - PROTAC
KW - Small molecule inhibitor
UR - http://www.scopus.com/inward/record.url?scp=85088810800&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85088810800&partnerID=8YFLogxK
U2 - 10.1186/s13045-020-00924-z
DO - 10.1186/s13045-020-00924-z
M3 - Review article
C2 - 32718354
AN - SCOPUS:85088810800
SN - 1756-8722
VL - 13
JO - Journal of Hematology and Oncology
JF - Journal of Hematology and Oncology
IS - 1
M1 - 103
ER -