Proteolysis-targeting chimeras (PROTACs) in cancer therapy

Abstract

Proteolysis-targeting chimeras (PROTACs) are engineered techniques for targeted protein degradation. A bifunctional PROTAC molecule with two covalently-linked ligands recruits target protein and E3 ubiquitin ligase together to trigger proteasomal degradation of target protein by the ubiquitin-proteasome system. PROTAC has emerged as a promising approach for targeted therapy in various diseases, particularly in cancers. In this review, we introduce the principle and development of PROTAC technology, as well as the advantages of PROTACs over traditional anti-cancer therapies. Moreover, we summarize the application of PROTACs in targeting critical oncoproteins, provide the guidelines for the molecular design of PROTACs and discuss the challenges in the targeted degradation by PROTACs.

Development of Rapid and Facile Solid‐Phase Synthesis of PROTACs via a Variety of Binding Styles

“…These are typical PROTACs with alkyl linkers that contain JQ1 as a POI ligand and degrade the target protein, bromodomain‐containing 4 (BRD4) [20] . A number of PROTACs targeting BRD4 have been reported for cancer therapy [21] . Most of them contain an alkyl linker, [18,19,22] while others are based on a PEG linker, [23] a photoswitchable azobenzene type, [24] or dihydropyrazine [25] formed by cyclization of trans ‐cyclo‐octene with tetrazine.…”

“…[20] A number of PROTACs targeting BRD4 have been reported for cancer therapy. [21] Most of them contain an alkyl linker, [18,19,22] while others are based on a PEG linker, [23] a photoswitchable azobenzene type, [24] or dihydropyrazine [25] formed by cyclization of trans-cyclo-octene with tetrazine. In the reported dBET1 and dBET6, thalidomide was used as the E3 ligand, but the CÀ O bond of thalidomide is possibly more unstable in buffer (pH 7.4) and human plasma than the CÀ N bond of pomalidomide.…”

LIM Kinases, Promising but Reluctant Therapeutic Targets: Chemistry and Preclinical Validation In Vivo

“…A potential answer to these problems could lie in the design and synthesis of LIMK specific PROTACs (Proteolysis-targeting chimeras). Although this strategy has been widely applied to different "undruggable" protein targets [68], relatively few papers have explicitly dealt with kinase degradation [69]. In the case of LIMK inhibition, a clear advantage is that instead of only targeting the active site to decrease or totally inhibit enzyme activity, a LIMK specific PROTAC would lead to the ubiquitination and degradation of the protein in the cell.…”

CRL4CRBN E3 Ligase Complex as a Therapeutic Target in Multiple Myeloma

“…To date, degronimids and other PROTACs are being studied extensively in a broad spectrum of hematologic malignancies and other cancers in preclinical studies [ 104 , 105 , 106 ]. In 2019, the first potential PROTAC-based drugs entered the first-in-human clinical trial in metastatic and castration-resistant prostate cancer (ARV-110; NCT03888612) and advanced breast cancer (ARV-471; NCT04072952), resulting in acceptable toxicity profile and the first evidence of the PROTACs’ clinical activity [ 107 , 108 ].…”