Current Challenges in Small Molecule Proximity-Inducing Compound Development for Targeted Protein Degradation Using the Ubiquitin Proteasomal System

Abstract

Bivalent proximity-inducing compounds represent a novel class of small molecule therapeutics with exciting potential and new challenges. The most prominent examples of such compounds are utilized in targeted protein degradation where E3 ligases are hijacked to recruit a substrate protein to the proteasome via ubiquitination. In this review we provide an overview of the current state of E3 ligases used in targeted protein degradation, their respective ligands as well as challenges and opportunities that present themselves with these compounds.

Single amino acid–based PROTACs trigger degradation of the oncogenic kinase BCR–ABL in chronic myeloid leukemia (CML)

“…PROTAC technology has garnered considerable attention and interests in the drug discovery industry because of its advantages in targeting undruggable proteins, recyclability, and overcoming drug resistance ( 13 , 27 ). However, this approach has also manifested several pressing shortcomings such as poor cell permeability because of the larger molecular weight of PROTAC compounds made of three components, limited number of E3 ligases currently available for PROTACs, and the lack of degradation speed control ( 13 , 15 , 18 , 21 ). In this study, we demonstrate the utility of the N-end rule–based PROTACs in BCR–ABL degradation, which can be further adjusted via different amino acids ( Fig.…”

“…, PEG) in the middle, PROTACs consist of a moiety for recruiting an E3 ubiquitin (Ub) ligase and a ligand for the target protein, bringing an E3 Ub ligase to a target protein to trigger substrate ubiquitylation and subsequent destruction ( 10 , 11 , 12 , 13 ). Although the ligands for target proteins have been extensively developed previously, the degradation motifs responsible for recruiting E3 ligase remain underdeveloped for the application in PROTACs ( 13 , 14 , 15 ). Thus far, the degradation signals have been largely restricted to two E3 Ub ligases, VHL (∼30%) and CRBN (∼60%) ( 16 ), which have certain limitations because of the cell- or tissue-specific expression ( 17 ).…”

PROTACs: A novel strategy for cancer drug discovery and development

“…[12][13][14][15][16][17][18] TPD has entered its third decade with both opportunities and challenges. [19][20][21][22][23][24][25][26][27][28] TPD techniques rely on the ubiquitin-proteasome system (UPS), which couples ubiquitylation, catalyzed by E1 activating enzyme, E2 conjugate enzyme and E3 ligase, and proteasome for degradation of target substrates. [29][30][31][32][33][34][35][36][37][38][39][40][41] The concept of PROTAC was first proposed in 2001, and the PROTAC technology has developed rapidly in the past 20 years.…”

“…The most representative alternative approach is the development of targeted protein degradation (TPD), with proteolysis targeting chimeras (PROTACs) as a typical example 12–18 . TPD has entered its third decade with both opportunities and challenges 19–28 . TPD techniques rely on the ubiquitin–proteasome system (UPS), which couples ubiquitylation, catalyzed by E1 activating enzyme, E2 conjugate enzyme and E3 ligase, and proteasome for degradation of target substrates 29–41 …”

“… 12 , 13 , 14 , 15 , 16 , 17 , 18 TPD has entered its third decade with both opportunities and challenges. 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 TPD techniques rely on the ubiquitin–proteasome system (UPS), which couples ubiquitylation, catalyzed by E1 activating enzyme, E2 conjugate enzyme and E3 ligase, and proteasome for degradation of target substrates. 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 …”