User:Sarah5085/Proteolysis targeting chimera

I added a lot of links/general cleanup in the article as well.

What I want to work on for my article:

Update Mechanism of Action section:

- Needs more citations and expansion

- Maybe combine this section with a structure section. Include warheads and linkers?

- Needs to talk about more than the UPS. How exactly does the PROTAC target the protein? says nothing about how PROTAC links the POI to the E3 ligase

Design/Development

- Could be interesting to include this because so much goes into the design of PROTACs

- Talk about different E3 ligases used, linker length, and warhead variations

- Need to collect some more sources to see if this could be a lengthy enough section

- Maybe add advances in clinical trials. Arvinas has two degraders in clinical trials, I have to do more research to see how many more are also.

Formation of a ternary complex between the protein of interest, PROTAC, and E3 ligase is often evaluated to characterize PROTAC activity because it often leads to ubiquitination and subsequent degradation of the targeted protein. Hook effect is often observed with high concentrations of PROTACs due to the bifunctional nature of the degrader.

Benefits (add to introduction)

- Basically talk about why PROTACs would be used over traditional inhibitors

- Need to find some sources for this, same issue with design section where it may not make sense to have a long section about this. If anything this could be expanded upon in the intro

Intro section

- Add more about the history maybe, could be interesting. Also there's some incorrect facts about thalidomide?? Will need to go over everything to make sure proper links and citations.

Add to list of E3 ligases used to create PROTACs: DCAF15, DCAF16, RNF114. I would also change the order of the list on the wikipedia article to make VHL and cereblon go first, also use abbreviation of cereblon to give it continuity. I think another sentence mentioning that VHL and CRBN are the main E3 ligases targeted would also be helpful. Could be cool to put that optimization using cell-specific E3 ligases is being investigated (maybe this could go with design and development).

Articles I can use

This article is about using PROTACs specifically for cancer, but it has a couple good sections about design/development and mechanism of action that I can use.

Using other article:

This one:

Lead
A proteolysis targeting chimera (PROTAC) is a heterobifunctional small molecule composed of two active domains and a linker, capable of removing specific unwanted proteins. Rather than acting as a conventional enzyme inhibitor, a PROTAC works by inducing selective intracellular proteolysis. PROTACs consist of two covalently linked protein-binding molecules: one capable of engaging an E3 ubiquitin ligase, and another that binds to a target protein meant for degradation. Recruitment of the E3 ligase to the target protein results in ubiquitination and subsequent degradation of the target protein via the proteasome. Because PROTACs need only to bind their targets with high selectivity (rather than inhibit the target protein's enzymatic activity), there are currently many efforts to retool previously ineffective inhibitor molecules as PROTACs for next-generation drugs.

Initially described by Kathleen Sakamoto, Craig Crews and Ray Deshaies in 2001, the PROTAC technology has been applied by a number of drug discovery labs using various E3 ligases, including pVHL, CRBN , Mdm2, beta-TrCP1, DCAF15, DCAF16, RNF114, and c-IAP1. Yale University licensed the PROTAC technology to Arvinas in 2013–14.

In 2019, Arvinas put two PROTACs into clinical trials, ARV-110, an androgen receptor degrader, and ARV-471, an estrogen receptor degrader.

Mechanism of Action
PROTACs achieve degradation through "hijacking" the cell's ubiquitin–proteasome system (UPS) by bringing together the target protein and the E3 ligase.

First, the E1 ligase activates and conjugates the ubiquitin to the E2 ligase. The E2 ligase then forms a complex with the E3 ligase. The E3 ligase targets proteins and covalently attaches the ubiquitin to the protein of interest. Eventually, after a ubiquitin chain is formed, the protein is recognized and degraded by the 26S proteasome. PROTACs take advantage of this cellular system by putting the protein of interest in close proximity to the E3 ligase to catalyze degradation.

Unlike traditional inhibitors, PROTACs have a catalytic mechanism, with the PROTAC itself being recycled after the targeted protein is degraded.

Design and Development
The protein targeting warhead, E3 ligase, and linker must all be considered for PROTAC development. Varying either warhead or the linker individually can have drastic effects on PROTAC performance. Formation of a ternary complex between the protein of interest, PROTAC, and E3 ligase may be evaluated to characterize PROTAC activity because it often leads to ubiquitination and subsequent degradation of the targeted protein. Hook effect is commonly observed with high concentrations of PROTACs due to the bifunctional nature of the degrader.

Currently, cVHL and CRBN have been used in preclinical trials as E3 ligases. However, there still remains hundreds of E3 ligases to be explored, with some giving the opportunity for cell specificity.

Benefits
Compared to traditional inhibitors, PROTACs display multiple benefits that make them desirable drug candidates. Due to their catalytic mechanism, PROTACs can be administered at lower dosages compared to their inhibitor analogues. Some PROTACs have been shown to be more selective than their inhibitor analogues, reducing off-target effects. PROTACs have the ability to target previously undruggable proteins, as they do not need to target catalytic pockets. This also helps prevent mutation-driven drug resistance often found with enzymatic inhibitors.