Advancing Strategies for Proteolysis-Targeting Chimera Design

Abstract

Proteolysis-targeting chimeras (PROTACs) have shown great therapeutic potential by degrading various disease-causing proteins, particularly those related to tumors. Therefore, the introduction of PROTACs has ushered in a new chapter of antitumor drug development, marked by significant advances over recent years. Herein, we describe recent developments in PROTAC technology, focusing on design strategy, development workflow, and future outlooks. We also discuss potential opportunities and challenges for PROTAC research.

Design and Evaluation of a Low Hydrogen Bond Donor Count Fragment Screening Set to Aid Hit Generation of PROTACs Intended for Oral Delivery

“…Multiple publications suggest that a low HBD count is a key contributing factor to achieving oral bioavailability for PROTACs (or bRo5 molecules). − ,, We considered that, to maximize the chances of developing PROTACs demonstrating adequate oral bioavailability, the desirable number of HBDs in a PROTAC structure should be less than or equal to 2. Considering that most described E3 ligase ligands contain at least 1 HBD, we defined a desirable “low HBD” count for appropriate fragment starting points (targeting orally administered PROTACs) to be between 0 and 1.…”

Drug Discovery Targeting Nuclear Receptor Binding SET Domain Protein 2 (NSD2)

“…253−259 PROTACs exert their function commonly through three steps: first, the formation of POI−PROTAC− E3 ligase ternary complexes, then induction of the polyubiquitylation of POIs, followed by the recognition and degradation of polyubiquitylated POIs by the 26S proteasome. 260,261 Compared to traditional small-molecule inhibitors, PROTACs possess several advantages 244,250,253 including that (1) PROTACs can induce the degradation of proteins, even those targets currently undruggable, providing new therapeutic options for various diseases; (2) PROTACs act through an "event-driven" mode instead of an "occupancy-driven" mode, thereby displaying their potency at a catalytic amount with potential to mitigate or avoid the off-target side effects; and (3) PROTACs can improve the selectivity for POIs toward other subtypes or proteins sharing similar active structures, further reducing the off-target toxicity. In recent years, significant advances have been achieved in the field of PROTAC technologies to develop novel degraders inducing the degradation of numerous disease-related targets such as AR, ER, BRD4, EZH2, BTK, EGFR, etc.…”

“…250,251,255 More than 18 PROTACs have entered clinical trials, of which the most advanced is an ER degrader ARV-471 in phase III clinical trials. 249,261 The PROTAC technology has also been applied for inducing NSD3 degradation based on a potent and selective NSD3-PWWP1 antagonist 46 (BI-9321, Figure 16). 262,263 In 2022, compound MS9715 (55, Figure 23) was designed and The cocrystal structure of the NSD2-PWWP1 domain in complex with 14 (UNC6934) revealed that the pyrimidine ring (marked by the red circle) points into the solvent-exposed region (Figure 24, PDB ID: 6XCG).…”

“…Over the past decade, the PROTAC technology has been emerging as a novel efficient strategy for the treatment of many diseases by inducing the degradation of target proteins via the ubiquitin–proteasome system (UPS), including those target proteins that were previously described as “undruggable”. − PROTACs, characterized by heterobifunctional small molecules, are composed of a ligand for the protein of interest (POI), a ligand for an E3 ligase, such as von Hippel–Lindau (VHL), cereblon (CRBN), mouse double minute 2 homologue (MDM2), a cellular inhibitor of apoptosis protein-1 (cIAP1), etc ., to recruit the UPS, and a linker for connecting the two ligands. − PROTACs exert their function commonly through three steps: first, the formation of POI–PROTAC–E3 ligase ternary complexes, then induction of the polyubiquitylation of POIs, followed by the recognition and degradation of polyubiquitylated POIs by the 26S proteasome. , Compared to traditional small-molecule inhibitors, PROTACs possess several advantages ,, including that (1) PROTACs can induce the degradation of proteins, even those targets currently undruggable, providing new therapeutic options for various diseases; (2) PROTACs act through an “event-driven” mode instead of an “occupancy-driven” mode, thereby displaying their potency at a catalytic amount with potential to mitigate or avoid the off-target side effects; and (3) PROTACs can improve the selectivity for POIs toward other subtypes or proteins sharing similar active structures, further reducing the off-target toxicity. In recent years, significant advances have been achieved in the field of PROTAC technologies to develop novel degraders inducing the degradation of numerous disease-related targets such as AR, ER, BRD4, EZH2, BTK, EGFR, etc . ,, More than 18 PROTACs have entered clinical trials, of which the most advanced is an ER degrader ARV-471 in phase III clinical trials. , …”

The Quest for Oral PROTAC drugs: Evaluating the Weaknesses of the Screening Pipeline

“…PROTACs (Proteolytic Targeting Chimeras), hereafter often addressed as degraders, are heterobifunctional molecules capable of inducing E3 ligase-mediated ubiquitination and subsequent degradation of a target protein (protein of interest or POI). Their unconventional catalytic mode of action and the associated advantages made PROTACs a new therapeutic modality, awakening huge interest in drug discovery. , The potential of PROTACs to address undruggable targets such as proteins with shallow surfaces, often involved in protein–protein interaction (PPI), and even scaffold proteins, other than the ability to target resistant cancer forms, , piqued the interest of both pharma/biotech industries and academia. , Remarkably, PROTACs possess large and flexible structures, which introduce notable challenges in concurrently optimizing solubility and cellular permeability. Specifically, the pursuit of increased permeability through heightened lipophilicity can potentially result in diminished solubility and metabolic stability. , …”