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

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 substoichiometric 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.

N6-methyladenosine methyltransferases: functions, regulation, and clinical potential

“…Thus, future efforts aimed at inhibiting the METTL3-eIF3h association may lead to the development of new cancer therapies. Notably, Proteolysis targeting chimeras (PROTACs), which are heterobifunctional small molecules that degrade proteins of interest through ubiquitin proteasome system, are another promising technology for the development of m6A methyltransferase-targeting therapeutics [ 161 ]. In addition, although this review focuses mostly on m6A methyltransferases, studies of m6A erasers have identified several potent inhibitors targeting the demethylase FTO in acute myeloid leukemia [ 162 , 163 ].…”

Gene Transcription as a Therapeutic Target in Leukemia

“…The abovementioned approaches including inhibition of protein–protein interactions are partially successful preclinically but less often clinically ( Table 4 ). One of the most promising approaches that recently emerged for hematologic malignancies is PROTACs (proteolysis-targeting chimeras) [ 237 ]. PROTACs are artificial heterobifunctional small molecules that utilize the ubiquitin proteasome system to degrade the proteins of interest.…”

“…Because of their ability to target mutant or undruggable proteins including fusion proteins, PROTACs can be therapeutically advantageous compared to enzymatic inhibitors. The efficacy of this technology has been reported for inhibition of numerous oncoproteins in a variety of tumors including blood malignancies (reviewed in [ 237 ]). The safety, selectivity, and therapeutic efficacy of PROTACs in hematologic malignancies emerge as hot problems.…”

Drug design targeting active posttranslational modification protein isoforms

“…Although no PTM protein isoform‐specific PROTAC has been reported, a number of PROTACs targeting PTM modification enzymes with potent selectivity, including CDK and BCR‐ABL kinases, and histone methylation enzyme complex PRC2, have been reported 366 . For example, selectively targeting cyclin‐dependent kinase 6 (CDK6) with ATP‐competitive small molecules has been challenging by virtue of the presence of an identical ATP‐binding site in its close homology cyclin‐dependent kinase 4 (CDK4).…”