1. Design and pharmaceutical applications of proteolysis-targeting chimeric molecules
Yuqing Liang, Kutty Selva Nandakumar, Kui Cheng Biochem Pharmacol. 2020 Dec;182:114211.doi: 10.1016/j.bcp.2020.114211.Epub 2020 Aug 29.
Proteolysis-targeting chimeras (PROTACs), the hetero-bifunctional compounds containing a specific ligand to bind the target protein, a suitable linker, and an E3 ubiquitin ligase substrate, are being developed for therapeutic applications. PROTACs hijack the catalytic activity of ubiquitin E3 ligases to mediate proteasome dependent degradation of selected protein of interest (POI), by bringing the ligase and POI into close spatial proximity and initiating the poly-ubiquitination process. Compared to the traditional small-molecule drugs, PROTACs reduce the problems of dosage, drug resistance, side effects and undruggable targets that could not be targeted pharmacologically. In this review, all the POIs, and peptide to small-molecule based PROTACs developed during the past two decades are summarized and directions for future development are discussed.
2. Chemical genetic control of protein levels: selective in vivo targeted degradation
John S Schneekloth Jr, Fabiana N Fonseca, Michael Koldobskiy, Amit Mandal, Raymond Deshaies, Kathleen Sakamoto, Craig M Crews J Am Chem Soc. 2004 Mar 31;126(12):3748-54.doi: 10.1021/ja039025z.
Genetic loss of function analysis is a powerful method for the study of protein function. However, some cell biological questions are difficult to address using traditional genetic strategies often due to the lack of appropriate genetic model systems. Here, we present a general strategy for the design and syntheses of molecules capable of inducing the degradation of selected proteins in vivo via the ubiquitin-proteasome pathway. Western blot and fluorometric analyses indicated the loss of two different targets: green fluorescent protein (GFP) fused with FK506 binding protein (FKBP12) and GFP fused with the androgen receptor (AR), after treatment with PROteolysis TArgeting Chimeric moleculeS (PROTACS) incorporating a FKBP12 ligand and dihydrotestosterone, respectively. These are the first in vivo examples of direct small molecule-induced recruitment of target proteins to the proteasome for degradation upon addition to cultured cells. Moreover, PROTAC-mediated protein degradation offers a general strategy to create "chemical knockouts," thus opening new possibilities for the control of protein function.
3. Phenyl-Glutarimides: Alternative Cereblon Binders for the Design of PROTACs
Jaeki Min, Anand Mayasundari, Fatemeh Keramatnia, Barbara Jonchere, et al. Angew Chem Int Ed Engl. 2021 Dec 13;60(51):26663-26670.doi: 10.1002/anie.202108848.Epub 2021 Nov 16.
Targeting cereblon (CRBN) is currently one of the most frequently reported proteolysis-targeting chimera (PROTAC) approaches, owing to favorable drug-like properties of CRBN ligands, immunomodulatory imide drugs (IMiDs). However, IMiDs are known to be inherently unstable, readily undergoing hydrolysis in body fluids. Here we show that IMiDs and IMiD-based PROTACs rapidly hydrolyze in commonly utilized cell media, which significantly affects their cell efficacy. We designed novel CRBN binders, phenyl glutarimide (PG) analogues, and showed that they retained affinity for CRBN with high ligand efficiency (LE >0.48) and displayed improved chemical stability. Our efforts led to the discovery of PG PROTAC 4 c (SJ995973), a uniquely potent degrader of bromodomain and extra-terminal (BET) proteins that inhibited the viability of human acute myeloid leukemia MV4-11 cells at low picomolar concentrations (IC50 =3 pM; BRD4 DC50 =0.87 nM). These findings strongly support the utility of PG derivatives in the design of CRBN-directed PROTACs.
