Talk:Proteolysis targeting chimera

Wiki Education Foundation-supported course assignment

This article was the subject of a Wiki Education Foundation-supported course assignment, between 7 January 2020 and 14 April 2020. Further details are available on the course page. Student editor(s): Rhartsou.

Above undated message substituted from Template:Dashboard.wikiedu.org assignment by PrimeBOT (talk) 02:48, 18 January 2022 (UTC)

Wiki Education Foundation-supported course assignment

This article was the subject of a Wiki Education Foundation-supported course assignment, between 8 September 2021 and 19 December 2021. Further details are available on the course page. Student editor(s): Sarah5085.

Above undated message substituted from Template:Dashboard.wikiedu.org assignment by PrimeBOT (talk) 02:48, 18 January 2022 (UTC)

Chimera -> Chimaera

I believe that Chimaera is the correct spelling. This might require a minor page move, too. RogueTeddy (talk) 09:33, 24 March 2019 (UTC)

I added a citation to the Mechanism section --Rhartsou (talk) 20:26, 10 April 2020 (UTC)

College writing course

Hi, I am editing this page as part of a college writing course. I plan on updating the introduction, mechanism of action, and possibly including a development section. I'll link some of the new references I'll include later. Sarah5085 (talk) 15:22, 16 November 2021 (UTC).

@Sarah5085: Happy editing, and feel free to ask me if you need any help! --ἀνυπόδητος (talk) 07:37, 17 November 2021 (UTC)

Benefits

One claim is: " This also helps prevent mutation-driven drug resistance often found with enzymatic inhibitors." That does not follow at all. Any selection pressure to keep a protein functional applies equally to it being inhibited directly or indirectly targeted for degradation. In either case some sort of binding is required and so in either case there is just as much selection pressure to mutate the binding site away from the binding regardless of how the binding causes issues as the same binding mutations "cost the same" amount of biological fitness and have the same reward in persevering enzyme function. I.e. the difference in evolutionary selection pressure and risk + rate + reward of mutation is irrelevant if a small molecule binder causes inhibition directly, targets it for degradation, is a transponder that calls in a nano-scale smart missile, or magically summons little demons who simply keep the substrates from reaching the enzymes active site like little goalies intercepting shots. Any mechanism of enzyme function reduction real or purely imaginary is irrelevant in its difference on mutation selection pressure so long as the basis for initiating of the mechanism is binding. In all such cases the same selection pressures and mutational possibilities are equally in play and have the same risk and rewards. Worse, the statement as situated implies that because degraders can bind outside of the active site this reduces mutational issues, which is doubly wrong -- the non-active site surfaces of a protein are often orders of magnitude more permissive in mutational tolerance then the active site, as the active site is the most precisely tuned and delicate portion of the entire protein. This has been found with allosterically regulating enzyme inhibitors -- they bind outside of the active site and cause a change in protein conformation to shut it down. Such allosteric enzyme inhibitors can be extremely useful especially as they are typically non-competitive binders v.s. substrate, but in cases where there is strong mutation selection pressure, on average they are far more easily and quickly defeated by lower fitness-cost mutations then typical active site binding inhibitors.

Thus, in leu of a really good citation proving this at-face, on-paper, doubly-wrong statement currently made I think this statement should be removed. Additionally a "really good citation" would be one that actually has data to back up such an assertion instead of such an assertion just dumped into a paper unproven by a protac author who is "selling their wares" with lofty (but unproven) statements as many of us scientific authors are want to do from time to time very much to the discredit of what has become of modern science.162.220.42.222 (talk) 18:59, 26 May 2022 (UTC)

Dear Sir, thank you very much for your comment. As I can see from your contributions that you are quite knowledgeable in science, I would advise you to just go ahead and change things you think need to be changed. In this case, the sentence you are referring to is unsourced, so it should be removed per Wikipedia's guidelines anyway. As a more junior scientist, I find your line of reasoning a bit hard to follow, though I do understand the overarching points that 1. even when molecules target enzymes at their non-active site, they can still be subject to mutations and 2. the sentence you pointed out is probably stemming from self-promotion rather than a scientific truth. Abnormalcy333 (talk) 07:06, 27 May 2022 (UTC)

Hi, there are many flaws in your comment, I'm not saying that what you're saying is wrong per se but you have many omissions which make the conclusion, misleading.

> This also helps prevent mutation-driven drug resistance often found with enzymatic inhibitors.

> your comment

Look I agree things are not clear cut and PROTACS might not necessarily be universally better than inhibitors/agonists.

But contrary to what your comment make it seems, the two strategies are far from being equal and can significantly differ.

For example, let's say we are fighting cancer and we have an oncogene X.

The oncogene create the example protein X.

classic strategy, we want to prevent the pharmacology of X.

e.g let's says it 'binds'/activate the mTOR1C pathway which stimulate cancer proliferation.

We currently would use a potent inhibitor of mTOR(s), such as rapamycin.

instead with the protacs we would need to design a new ligand that binds to the onco protein X.

it binds and destroy/catabolyze the protein making it mostly ineffective.

Can you see how superior that approach is here?

let's consider:

1) that rapamycin blocks mTOR in every cells even non-cancerous cells. This is toxic and leads to side effects.

Instead the PROTAC has no effects on healthy cells, this is disruptive.

2) that rapamycin like many agonists in general is coarse grained, it lacks selectivity. X only agonize mTOR1c but rapamycin also agonize other subreceptors including mTOR2, leading to more side effects.

This class of problem is non existent for the PROTAC since protein X is not a receptor per se and has no sub-receptors or if it has, they're pointless, it's a protein not a proper ligand.

3) protein X could very well have other pharmacological effects, including binding to other ligands of which we have no known antagonist, and intrinsic effects such as e.g being oxidative, etc..

Again the PROTAC bypass all those classes of problems.

4) agonists/antagonists are subjects to homeostatic compensations/tolerances

Those 3 properties are completely disruptive/revolutionnary.

You original argumentation is true, the oncogene can mutate to make the protac no longer bind to the new X variant but what are the odds of a specific effective mutation to that specific protein? a counter example would be e.g PNC-27 which doesn't develop much tolerance. To bind a protac shouldn't need an exact protein sequence match, a partial key fragment should be enough.

On the other hand via an inhibitor, the oncogene cannot bypass it since the receptor is blocked (few blockers are displaceable/reversible).

Your argument on allosteric modulators and the mutability resilience when outside of the active ligand site is interesting but does not take into account the 4 reasons I enumerated. However a more pedagogical/sourced explanation of your argument would be welcome as it is interesting.

What I am not understanding however is how PROTAC differs vs an antigen/antibody.

I mean I understand that one is a catalysis and one is an immune/immune-like action, but if antibody permeate the cell then they do literally the same thing.

I heard antibodies can have effectiveness lowered by the immune system but otherwise why would protacs be better than antibodies? 2A04:CEC0:1135:9A82:3DB3:1A95:8F39:5AB1 (talk) 03:01, 7 January 2023 (UTC)