The Chemical Probes Portal now includes several PROTACs in the list of recommended chemical probes and even more are under review by our Scientific Advisory Board.

Proteolysis Targeted Chimeras (PROTACs) are bifunctional protein degraders that hold promise for elucidating disease mechanisms as well as providing new leads for therapeutics. These molecules have a ligand for the target protein, and a ligand for the cellular proteolysis machinery – often an E3 ubiquitin ligase – connected by a flexible linker. PROTACs bring the target protein and the degradation machinery together, resulting in the destruction of the target.

PROTACs act as catalysts for degradation, and are not usually destroyed themselves. They are often therefore highly efficient even if the interaction with the target protein has low potency. This means they can be effective in cells at lower concentrations than equivalent conventional probes.

PROTACs are a pharmacological alternative to RNA interference or inducible CRISPR for targeted depletion of proteins in cells. Through physically removing the protein, PROTACs also inhibit any structural roles of the protein within the cell, and so can be used to study scaffolding effects, in addition to a protein’s enzymatic activity.

Several new PROTACs have been added to the Chemical Probes Portal. These include CM11, which targets the E3 ubiquitin ligase VHL for auto-degradation, complementing the existing VHL inhibitor VH298. More are currently being reviewed by our Scientific Advisory Board and will be updated soon.

As PROTACs act differently to more conventional chemical modulators, their selection requires alternative criteria, including evidence and quantification of target degradation, measured by DC₅₀ and D_max values. PROTAC criteria for judging high quality compounds have been published by the Chemical Probes team, based on seminal publications, including the recent comprehensive contribution by Kostic and Jones (2020).

Please contact us with any feedback and submit a probe if you have a new PROTAC that could be included in the portal.

If you are an expert in the field and want to uphold high standards of research, please get in touch. We welcome suggestions or referrals for new Scientific Advisory Board members at faculty level or above.

Key publications:

Critical assessment of targeted protein degradation as a research tool and pharmacological modality by Milka Kostic and Lyn Jones (Trends in Pharmacological Sciences)
A critical evaluation of the approaches to targeted protein degradation for drug discovery by Rajesh Chopra, Amine Sadok and Ian Collins (Drug Discovery Today: Technologies)
PROTACs: great opportunities for academia and industry by Xiuyun Sun et al. (Signal Transduction and Targeted Therapy)
Homo-PROTACs: bivalent small-molecule dimerizers of the VHL E3 ubiquitin ligase to induce self-degradation by Chiara Maniaci et al. (Nature Communications)

protacs

The probe JQ1, which inhibits BET proteins BRD2, BRD3 and BRD4 and the PROTAC MZ1, which targets BRD4 for proteosome degradation by tethering it to the E3 ligase VHL.

Proactive towards PROTACs