A critical evaluation of the approaches to targeted protein degradation for drug discovery

Abstract

There is a great deal of excitement around the concept of targeting proteins for degradation as an alternative to conventional inhibitory small molecules and antibodies. Protein degradation can be undertaken by bifunctional molecules that bind the target for ubiquitin mediated degradation by complexing them with Cereblon (CRBN), von Hippel-Lindau or other E-3 ligases. Alternatively, E-3 ligase receptors such as CRBN or DCAF15 can also be used as a ‘template’ to bind IMiD or sulphonamide like compounds to degrade multiple context specific proteins by the selected E-3 ligases. The ‘template approach’ results in the degradation of neo-substrates, some of which would be difficult to drug using conventional approaches. The chemical properties necessary for drug discovery, the rules by which neo-substrates are selected by E-3 ligase receptors and defining the optimal components of the ubiquitin proteasome for protein degradation are still to be fully elucidate. Theis review will aim to critically evaluate the different approaches and principles emerging for targted protein degradation.

Systematic exploration of different E3 ubiquitin ligases: an approach towards potent and selective CDK6 degraders

“…14,15,19,20 The eld of proteolysis targeting chimeras (PROTACs) has made tremendous achievements and reached substantial milestones in the last years. [21][22][23][24][25][26][27][28][29] Briey, PROTACs are bifunctional small molecules, which comprise two linker-connected moieties that simultaneously bind a target protein and an E3 ubiquitin ligase. Frequently employed E3 ligase binders 3-6 which have successfully been utilized in PROTAC design are presented in Fig.…”

Structure-Based Design of a Macrocyclic PROTAC

“…The cyclizing part of the linker optimally fills an additional cavity created at the interface of the two proteins next to the ZA-loop of Brd4 BD2 (Figure 3 A and Supporting Information, Figure S6), which is in good agreement with the MD simulations (Figure 1 D and Supporting Information, Figure S2). The BSA at the macroPROTAC-1:VHL and macroPROTAC-1:Brd4 BD2 interfaces are 961 and 1064 2 , respectively, which brings the total BSA to 2686 2 . Taken together, these findings could explain the high cooperativity of VHL:macroPROTAC-1:Brd4 BD2 .…”

“…Targeted protein degradation is a powerful new modality of chemical biology and drug discovery. [1,2] PROTACs are bifunctional molecules composed of a ligand for a target protein of interest, and a ligand for an E3 ubiquitin ligase, joined by a flexible linker. Recruitment of a protein close to an E3 ligase hijacks the ligase catalytic activity, leading to the tagging of the target protein by ubiquitination and subsequent proteasomal degradation.…”

Structure‐Based Design of a Macrocyclic PROTAC

“…Collectively,t hese interactions result in ab uried surface area (BSA) between the two proteins of 681 2 .T he MZ1-portion of macroPROTAC-1 binds in an identical Sshaped conformation to the uncyclized PROTAC,r etaining the H-bond between His437 Brd4(BD2) and an oxygen atom on the PEG-3 linker.T he cyclizing part of the linker optimally fills an additional cavity created at the interface of the two proteins next to the ZA-loop of Brd4 BD2 ( Figure 3A and Supporting Information, Figure S6), which is in good agreement with the MD simulations ( Figure 1D and Supporting Information, Figure S2). TheB SA at the macroPROTAC-1:VHL and macroPROTAC-1:Brd4 BD2 interfaces are 961 and 1064 2 ,respectively,which brings the total BSA to 2686 2 . Taken together, these findings could explain the high cooperativity of VHL:macroPROTAC-1:Brd4 BD2 .C loser examination of the additional linker revealed potential clashes with the ZA-loop,w hich could explain the loss in binding affinity with the BET bromodomains.W ithin the ZA-loop, the side chain of Leu387, as well as the carbonyl oxygens of both Gly386 and Leu385, are less than 3.5 from the newly added linker.…”

“…Targeted protein degradation is apowerful new modality of chemical biology and drug discovery. [1,2] PROTACs are bifunctional molecules composed of al igand for at arget protein of interest, and al igand for an E3 ubiquitin ligase, joined by af lexible linker.R ecruitment of ap rotein close to an E3 ligase hijacks the ligase catalytic activity,leading to the tagging of the target protein by ubiquitination and subsequent proteasomal degradation. [3][4][5] PROTACsa re emerging as attractive chemical probes and therapeutics,d efined by ac atalytic and sub-stoichiometric rather than occupancybased mode of action, leading to an extended duration of action.…”