Protac-Induced Protein Degradation in Drug Discovery: Breaking the Rules or Just Making New Ones?

Abstract

Targeted protein degradation, using bifunctional small molecules (Protacs) to remove specific proteins from within cells, has emerged as a novel drug discovery strategy with the potential to offer therapeutic interventions not achievable with existing approaches. In this Perspective, the brief history of the field is surveyed from a drug discovery perspective with a focus on the key advances in knowledge which have led to the definition and exemplification of protein degradation concepts and their resulting applications to medicine discovery. The approach has the potential to bring disruptive change to drug discovery; the many potential advantages and outstanding challenges which lie ahead of this technology are discussed.

PDZ Domains as Drug Targets

“…[93] Finally, two strategies for PPI modulation were recently described but have not yet been applied toward PDZ domain proteins. [95] In the next sections, the applications of PDZ targeting in the treatment of neurological diseases and cancer treatment will be discussed, focusing on the development of orthosteric inhibitors. [94] In the second, the signaling pathway is modified by a direct reduction of one of the interacting proteins using proteolysis targeting chimera (PROTAC).…”

Molecular design opportunities presented by solvent‐exposed regions of target proteins

“…Targeted protein degradation, using heterobifunctional small molecules (PROTACs) to remove protein targets from within cells, has emerged as a novel strategy for drug development, with the opportunity of providing therapeutic interventions not achievable with existing occupancy‐based enzyme inhibition approaches . Small‐molecular‐weight synthetic PROTACs ( 185‐189 ) have been used to selectively degrade various specific proteins (Figure ), including pirin, sirt2, BET protein, androgen receptor, and BRD4 protein …”

“…into one molecule, to take advantage of the presence of large hydrophobic patches at the HDAC surface rim. 122 Some encouraging results have been reported (Figure 22), such as dual-acting HDAC and topoisomerase II inhibitor On the basis of these analyses, a structure-based hybridization strategy was used to discover novel Mcl-1/Bcl-xL dual inhibitors (159,160) with a suitable linker based on 157 and 158 ( Figure 22). Notably, compound 160 displayed the potent dual-inhibitory activities (Mcl-1, IC 50 = 0.088 μM; and Bcl-xL, IC 50 = 0.0037 μM) ( Figure 23).…”

Proteolysis‐targeting chimeras in drug development: A safety perspective

“…Another PROTAC property includes the potential to target any type of protein as long as a small molecule, low MW ligand with appropriate affinity can be generated for the POI. This has been discussed in detail in several recent reviews (Churcher, 2018;Collins, Wang, Caldwell, & Chopra, 2017;Mayor-Ruiz & Winter, 2019;Ohoka, Shibata, Hattori, & Naito, 2016;Pettersson & Crews, 2019;Schapira, Calabrese, Bullock, & Crews, 2019).…”

“…Proteolysis‐targeting chimeras (PROTACs) are drug‐like molecules that induce the degradation of proteins (Bondeson et al, ; Churcher, ; Deshaies, ; Mayor‐Ruiz & Winter, ; Paiva & Crews, ; Pettersson & Crews, ). They work by bringing into close proximity an E3 ligase and a protein of interest (POI), inducing ubiquitination of the POI and its subsequent degradation via the proteasome.…”