PROTAC targeted protein degraders: the past is prologue

Abstract

Targeted protein degradation (TPD) is an emerging therapeutic modality with the potential to tackle disease-causing proteins that have historically been highly challenging to target with conventional small molecules. In the 20 years since the concept of a proteolysis-targeting chimera (PROTAC) molecule harnessing the ubiquitin–proteasome system to degrade a target protein was reported, TPD has moved from academia to industry, where numerous companies have disclosed programmes in preclinical and early clinical development. With clinical proof-of-concept for PROTAC molecules against two well-established cancer targets provided in 2020, the field is poised to pursue targets that were previously considered ‘undruggable’. In this Review, we summarize the first two decades of PROTAC discovery and assess the current landscape, with a focus on industry activity. We then discuss key areas for the future of TPD, including establishing the target classes for which TPD is most suitable, expanding the use of ubiquitin ligases to enable precision medicine and extending the modality beyond oncology.

Overcoming Cancer Drug Resistance Utilizing PROTAC Technology

“…Thus, there is an urgent need to develop novel treatment strategies and therapeutic modalities ( Vasan et al, 2019 ). The advent of PROTAC technology has been paradigm-shifting in drug discovery, by offering many potential advantages over occupancy-driven protein inhibitors ( Békés et al, 2022 ). PROTACs are being developed to target a number of clinically relevant targets and more than a dozen of them have been advanced to clinical trials ( Mullard, 2021 ; Garber, 2022 ), demonstrating the great promise of this new therapeutic modality.…”

FDA-Approved Small Molecule Compounds as Drugs for Solid Cancers from Early 2011 to the End of 2021

“…It is worth noting that two of the presented molecules, i.e., adavosertib (formerly AZD1775 ) and pemrametostat (formerly GSK3326595 ), are characterized by a completely new mechanism of action, such as WEE1 G2 checkpoint kinase (WEE1) inhibition and protein arginine methyltransferase 5 (PRMT5) inhibition, respectively [ 271 , 272 ]. The next two agents, i.e., ARV-471 and giredestrant (also known as GDC-9545 ) are specifically designed to target and degrade the estrogen receptor (ER) during the treatment of patients with breast cancer [ 273 , 274 ]. It should be emphasized that ARV-471 is one of the first clinically evaluated proteolysis-targeting chimera (PROTAC) molecules.…”

“…This agent consists of two active domains joined by a linker, wherein one domain binds a protein of interest (POI) and the other binds an E3 ubiquitin ligase, resulting in an induction of selective intracellular proteolysis. The usage of PROTAC molecules improves oral exposure, efficacy and safety in the clinic [ 273 ]. Since protein kinases are a common molecular target in drug design, there are a lot of protein kinase inhibitors under development and clinical evaluation, for example, AKT inhibitor ipatasertib , known as GDC-0068 , or EGFR and HER2 inhibitor varlitinib , known as ARRY-334543 [ 275 , 276 ].…”

Development of an LC-MS/MS Method for ARV-110, a PROTAC Molecule, and Applications to Pharmacokinetic Studies

“…As a promising and appealing technology for targeted protein degradation, proteolysis-targeting chimeras (PROTACs) offer a chemical knockdown strategy for a protein of interest (POI). The PROTAC approach was first proposed in 2001 by Sakamoto et al [ 1 ] and remarkable developments have been made over the last 20 years [ 2 , 3 ]. Because PROTAC technology enables the elimination of the entire POI, it can potentially overcome the resistance to current treatments.…”

“…Many PROTACs have been validated in preclinical stages [ 2 ]. ARV-110 (bavdegalutamide), was the first PROTAC to enter clinical trials in 2019, which targets AR for the treatment of metastatic castration-resistant prostate cancer (mCRPC) [ 7 ].…”