Targeted protein knockdown using small molecule degraders

Abstract

Small molecule probes of biological systems have traditionally been designed to bind to and inhibit the active sites of their protein targets. While this class of pharmacological agents has been broadened by the development of a small number of allosteric and protein-protein interaction (PPI) inhibitors, conventional drug design still excludes ‘undruggable’ proteins that are neither enzymes nor receptors. Recent years have seen the emergence of new classes of small molecules that can target hitherto undruggable proteins by recruiting the cellular proteostasis machinery to selectively tag them for degradation. These molecules, especially the class known as Proteolysis Targeting Chimera (PROTACs), represent a paradigm shift in chemical genetics, but their most tantalizing potential is as novel therapeutic agents. This review briefly summarizes the preclinical development of small molecule-based protein degraders, and describes the recent improvements in the technology that have positioned PROTACs on the cusp of entering the clinic.

Thalidomide promotes degradation of SALL4, a transcription factor implicated in Duane Radial Ray syndrome

“…These findings can inform the development of new compounds that induce CRBN-dependent degradation of disease-relevant proteins but avoid degradation of developmental transcription factors such as SALL4, and thus have the potential for therapeutic efficacy without the risk of teratogenicity, a defining feature of this class of drugs. This is further relevant to the development of thalidomide-derived bifunctional small molecule degraders (commonly referred to as PROTACs) ( Raina and Crews, 2017 ), as we show that IMiD-based PROTACs (and novel IMiD derivatives such as CC-220) can be effective inducers of ZnF targets including SALL4 degradation ( Figure 1—figure supplement 1C ). Lastly, the surprising expansion in substrate repertoire for pomalidomide, suggests that IMiDs exhibit a large degree of polypharmacology contributing to both efficacy and adverse effects.…”

Surface Probing by Fragment-Based Screening and Computational Methods Identifies Ligandable Pockets on the von Hippel–Lindau (VHL) E3 Ubiquitin Ligase

“…Notably, optimized compounds binding to the new sites could also be converted into targeted protein degraders, i.e., PROTACs. 13 The presence of several ligandable pockets in VCB additionally sets an ideal, yet challenging, scenario to explore these and other binding sites using computational pocket detection methods. Thus, we next subjected VCB to a surface probing campaign using SiteMap, 28 FTMap, 29 , 30 and mixed-solvent MD.…”

The PROTAC technology in drug development

“…This proteolysis targeting chimera (PROTAC) consists of a ligand on an E3 ubiquitin ligase, a linker, and a ligand on targeted protein could be able to mediate the degradation of multiple molecules of RIPK2 via ubiquitin-proteasomal pathway. 15,52 To overcome the shortage of insufficient membrane permeability and stability of the peptide-based PROTACs, Hashimoto group focused on using cIAP1, which promotes ubiquitination and proteasomal degradation of interacting proteins. 44 Many of the small molecule-based PROTACs have been developed intensively to target the BET family proteins.…”

“…50 To date, small molecule-based PROTACs have been generated to recruit MDM2, cellular inhibitor of apoptosis protein 1 (cIAP1), CRBN (cereblon), and, of course, VHL (for review, see Toure and Crews 51 ). 15,52 To overcome the shortage of insufficient membrane permeability and stability of the peptide-based PROTACs, Hashimoto group focused on using cIAP1, which promotes ubiquitination and proteasomal degradation of interacting proteins. [53][54][55] They recruited a class of bestatin ester analogues (MeBS, methyl bestatin), a ligand binding to the baculoviral IAP repeat domains of cIAP1, to all-trans retinoid acid to target CRABP-I and II (cellular retinoic acid binding proteins-I and II).…”