Blocking Non-enzymatic Functions by PROTAC-Mediated Targeted Protein Degradation

Abstract

The non-enzymatic functions of target proteins play key roles in the regulation of various cell signaling pathways and are closely related to numerous human diseases. However, traditional small-molecule inhibitors generally target the catalytic functional domain directly and work by inhibiting the enzymatic function of the target proteins without affecting the nonenzymatic function. The recently emerging proteolysis targeting chimera (PROTAC) technology has the advantage of simultaneously regulating the enzymatic and non-enzymatic functions of target proteins, thus providing a potential strategy to make up for the deficiency of inhibitors and explore the new therapeutic profile by the target degradation. This perspective aims to specifically summarize and analyze recent progress in blocking non-enzymatic functions of target proteins by PROTAC-mediated degradation, highlighting representative case studies and discussing the pharmacological features originating from inhibition of the non-enzymatic functions.

Discovery of Potent and Selective WDR5 Proteolysis Targeting Chimeras as Potential Therapeutics for Pancreatic Cancer

“…41−45 Compared with occupancydriven small-molecule inhibitors that specifically target the enzymatic functions of the POIs, PROTACs pharmacologically induce the degradation of the POIs, resulting in the suppression of both the enzymatic and nonenzymatic functions of the POIs. 46,47 Recently, based on WDR5 WIN-site inhibitor OICR-9429, our group and Knapp group independently developed von Hippel−Lindau (VHL)-recruiting WDR5 PROTACs, such as MS33, MS67, and 8g (Figure 1). 48,49 By conducting a limited structure−activity relationship (SAR) study in mixed lineage leukemia rearranged (MLL-r) leukemia cells, we discovered MS67, a potent and selective VHLrecruiting WDR5 degrader, which effectively suppressed in vivo tumor growth in both MLL-r cell line xenograft and patient-derived xenograft (PDX) mouse models.…”

PROTACs: A novel strategy for cancer drug discovery and development

“…Since then, a series of novel and highly effective VHL E3 ligase ligands have been discovered and reported, typified by compounds VHL‐1–VHL‐8 (Figure 2) with improved lipophilicity 119,120,122 . The studies on the eutectic structure of the VHL ligand with the protein helps to locate the solvent‐exposed region, leading to revelation of four possible linking sites without negatively affecting the interaction between the protein and the corresponding ligand (Figure 2; PDB ID: 4W9H) 123–134 . These sites are (a) terminal amino; (b) sulfhydryl; (c) benzyl; and (d) phenolic hydroxyl group on the benzene ring 113,135–141 .…”

A Degron Blocking Strategy Towards Improved CRL4CRBN Recruiting PROTAC Selectivity**

“…By degrading rather than inhibiting targets, PROTACs result in the disruption of both enzymatic and nonenzymatic functions of proteins (such as scaffolding) or transcriptional functions of transcription factors. [5][6][7] The E3 ligase CRL4 CRBN has been widely used to generate heterobifunctional degraders against a range of targets, [8] with CRL4 CRBN based PROTACs advancing in the clinic and showing early signs of efficacy. [1,9] The focus on hijacking CRL4 CRBN stems from the availability of thalidomide-like derivatives (called immunomodulatory drugs IMiDs, or more recently, Cereblon E3 ligase modulators CELMoDs) that bind with high specificity to the substrate receptor Cereblon (CRBN).…”