PROTAC-Based Protein Degradation as a Promising Strategy for Targeted Therapy in Sarcomas

Abstract

Sarcomas are heterogeneous bone and soft tissue cancers representing the second most common tumor type in children and adolescents. Histology and genetic profiling discovered more than 100 subtypes, which are characterized by peculiar molecular vulnerabilities. However, limited therapeutic options exist beyond standard therapy and clinical benefits from targeted therapies were observed only in a minority of patients with sarcomas. The rarity of these tumors, paucity of actionable mutations, and limitations in the chemical composition of current targeted therapies hindered the use of these approaches in sarcomas. Targeted protein degradation (TPD) is an innovative pharmacological modality to directly alter protein abundance with promising clinical potential in cancer, even for undruggable proteins. TPD is based on the use of small molecules called degraders or proteolysis-targeting chimeras (PROTACs), which trigger ubiquitin-dependent degradation of protein of interest. In this review, we will discuss major features of PROTAC and PROTAC-derived genetic systems for target validation and cancer treatment and focus on the potential of these approaches to overcome major issues connected to targeted therapies in sarcomas, including drug resistance, target specificity, and undruggable targets. A deeper understanding of these strategies might provide new fuel to drive molecular and personalized medicine to sarcomas.

Targeting SWI/SNF Complexes in Cancer: Pharmacological Approaches and Implications

“…Several BRD9 PROTACs have been constructed and shown to exert anti-cancer effects [189]. In an initial attempt to generate a BRD9 PROTAC, GSK39, a molecule with a structure similar to I-BRD9 was conjugated to a ligand that binds the cereblon (CRBN) ubiquitin ligase complex [182,190].…”

Extracellular Interactors of the IGF System: Impact on Cancer Hallmarks and Therapeutic Approaches

“…Among these approaches, proteolysis-targeting chimeras (PROTACs) are heterobifunctional molecules composed of three modules: a ligand-binding domain for the protein of interest, a linker, and a ligand specific to the E3 ligase. PROTACs have already entered clinical trials and hold promise for overcoming the major limitations connected to standard targeted therapies, such as drug resistance, specificity or undruggable targets [ 140 , 141 ]. Specific PROTACs, named CPR3 and CPR4, have recently been designed to co-target the IGF1R and Src.…”

Pathology, Diagnosis, and Management of Sarcoma

“…The rarity of tumors and the paucity of actionable mutations obstruct the development of new systemic treatments for bone and soft tissue sarcomas. Mancarella et al reviewed targeted protein degradation (TPD), an innovative pharmacological modality, to alter protein abundance, based on the use of small molecules called degraders or proteolysis-targeting chimeras (PROTACs) [ 8 ]. In the review, features of PROTAC and PROTAC-derived genetic systems were discussed, as well as the potential of these approaches to overcome various problems of targeted therapies in sarcomas, including drug resistance, target specificity, and undruggable targets.…”