[isoprophlex]

https://en.m.wikipedia.org/wiki/AOH1996

Look at that molecular structure. Incredible.

Two amide bonds, a completely unremarkable aryl ether and an unsubstituted naphthalene ring system. No fussy weird metals or bonds that need pampering, no chiral carbon atom in sight.

You could probably pay someone a very modest amount of money to end up with kilograms of this stuff, and it would probably not degrade at all under ambient conditions.

I wouldn't be surprised if we soon see desperate, sick, rich people try this out on themselves, skipping FDA approval.

Beautiful, uplifting news. Let's hope the clinical trials proceed without issue.

[Terr_]

> Look at that molecular structure. Incredible. Two amide bonds, a completely unremarkable aryl ether and an unsubstituted naphthalene ring system.

Something about this delivery reminds of the business-card scene from Psycho [0].

> Look at that subtle off-white coloring, the tasteful thickness of it--Oh my God, it even has a watermark..."

[0] https://www.youtube.com/watch?v=cISYzA36-ZY

[janejeon]

Now let's see Paul Allen's molecule.

[deep_merge]

*American Psycho. Dude in Psycho didn’t use a business card.

[nine_k]

Only it's the inverse: no subtlety, no surprises, all plain.

[Terr_]

I'm not sure I'd describe that scene as actually containing amazing surprises of printing, typography, or subjective stylishness.

I see it as mockery of some maladjusted status-obsessed men as they fawn and suffer over trivial differences in pretty-much-identical plain white business cards. Every card says the same thing except for the name, and many of the things being described aren't even true. (For example, not embossed, no watermark, etc.)

[plibither8]

> Look at that molecular structure. Incredible.

I first thought it was a joke because of the two "HN" bonds hah, pardon me.

[teruakohatu]

Can you explain to a layman why works to kill tumors and not healthy cells?

[isoprophlex]

The idea is that cancer cells have this mutant DNA clamp[0], which rallies DNA repair mechanisms in cells. The molecule targets the mutant clamp, disabling repair mechanisms for tumor cells but not healthy cells.

We all should hope that it has high specificity for the mutant PCNA, and doesn't affect healthy cells... clinical trials will investigate this.

[0] https://en.m.wikipedia.org/wiki/Proliferating_cell_nuclear_a...

[mbreese]

I don’t think this is targeting a mutated version of PCNA… that would assume that all cancers had the same mutation.

Instead, this would target both healthy and cancerous cells. However, the idea is that the cancer cells are more susceptible to the drug. Healthy cells will be affected, but cancer cells will be affected more, and are more unstable, so losing PCNA will have more of an effect on the cancer cells.

The main idea is to do as much damage to the cancer cells while doing as little to normal cells as possible.

Edit: after reading the paper, the drug is targeting a cancer specific isoform of PCNA. This isn’t a mutation, but a slightly different form of the existing protein. Cancers tend to rely on this specific version, while healthy cells can use a different isoform (or both?). A selective inhibitor for this isoform would be cancer cell specific. There would still be some effect on healthy cells, but not as much as with a traditional cytotoxic chemotherapy.

[overnight5349]

Hold up, we've identified a mechanism that all cancer cells posses and healthy cells don't? That's almost unbelievable.

I wonder how something like that comes about? Is there something special about that isoform that is necessary for tumor growth or what?

[7moritz7]

I read it selectively initiates apoptosis based on that protein and only affects cancer cells but that might have been relayed incorrectly

Edit: exactly -> "It was created to target a specific variant of PCNA found only in cancer cells. This protein is crucial in the body for DNA repair, but targeting it was difficult because of its role in healthy cells. By going after only the variant, it may be possible to selectively target only cancer cells"

From Wikipedia

[piyh]

>"Moreover, the identification of a distinct isoform of PCNA associated with cancer cells has potentially opened a novel avenue for the development of new chemotherapeutics"

It is targeting a mutated version.

https://www.cell.com/cell-chemical-biology/fulltext/S2451-94...

[mbreese]

A distinct isoform does not necessarily mean a mutation.

The coding sequence for an isoform is part of the normal gene DNA sequence, but the cells can “choose” which version to make. In this case the caPCNA isoform is the form predominantly expressed in cancer cells.

(There is a mechanism where novel splicing isoforms can be produced by a mutation, but this doesn’t seem to be one of those.)

[pulse7]

It is written "no discernible side effects"... So we will see...

[elgenie]

The linked thread that follows explains it in layman's terms.

The drug developers noticed that (a class of) cancer cells involve a shape change in the molecule that clamps on to DNA strands for the purposes of replication and repair. The molecule targets that shape change and thus prevents (a class of) cancer cells from being able to maintain and replicate their DNA.

Cancel cells die and can't replicate = no cancer.

[kybernetikos]

Derek Lowe had a similar take:

"AOH1996 is a very unremarkable-looking molecule - to be honest, it looks like the sort of stuff that you used to see in old combinatorial chemistry libraries in the late 90s and early 2000s, a couple of aryl-rich groups strung together with amide bonds."

https://www.science.org/content/blog-post/new-mode-cancer-tr...

[BenFranklin100]

A key sentence:

“I hope that human cancers will prove vulnerable to this new mode of attack in the clinic, and that they are not able to mutate around it with new forms of caPCNA too quickly, either.”

Even if this does prove effective in humans, eventually cancer cell defenses will evolve to get around it.

[larkost]

I don't think that evolve is the right word here. It is not that cancers generally will develop to the point where this is no longer useful in humans. In a single human it is possible that some collection of cancer cells mutates in a way that makes them resistant or immune from this effect (e.g.: by not having the mutated PCNA), and so that strain will become the dominant cancer in that one person. It is also possible that this pathway is pretty common, and this drug does not help out much because of that. But because cancer is not spread (outside of some rare cases), this is not really going to "evolve" like viruses do.

[BenFranklin100]

Good clarification, thank you.

[solomatov]

>Even if this does prove effective in humans, eventually cancer cell defenses will evolve to get around it.

Cancer becomes tolerant to drugs separately for each patient. I.e. initially it isn't resistant, but the drug used on a patient puts evolutionary pressure on the cancer to work around the drug. What this means is that people have more months or years to live, which is great. (I am not a doctor).

[pastor_bob]

It's possible that this drug doesn't wipe out all cancer cells if effective, thus leading to the possibility of the cells eventually mutating. But it's not like cancer is some bacteria that can become universally resistant.

The ABVD regime starts with the same baseline on all hodgkin's lymphoma patients, and 'cures' cancer permanently in quite a large number of them.

[szundi]

Goal is to die for some other reason before cancer evades this

[jancsika]

I used to bullseye DNA clamps with AOH1996 back home.

[tigerlily]

> Two amide bonds, a completely unremarkable aryl ether and an unsubstituted naphthalene ring system.

I much prefer your description of the molecule than the one found on its Wikipedia page.

[isoprophlex]

Thanks! Even though I've been in software instead of chemistry for the last 8-or-so years, a structural diagram of a molecule still sings to me of bonds, torsion and symmetry :)

[ncann]

> I wouldn't be surprised if we soon see desperate, sick, rich people try this out on themselves, skipping FDA approval

I know nothing about the FDA but for things like terminal cancer treatment, shouldn't there be a blanket exemption for "if the patient so wish, they can take whatever drugs they want even if unapproved"? When facing certain death, what's the worst that can happen? You die a bit sooner?

[adebiase44]

There is compassionate use: https://www.cancer.org/cancer/managing-cancer/making-treatme....

[thatguy0900]

The worst that can happen is a industry springing up around giving terminally ill scared desperate people suger pills at a 10000% markup

[mrguyorama]

The concern isn't about killing people already dying of cancer, but rather allowing literal snake oil salesmen to target people dying of cancer and ready to extract all possible wealth from dying people.

[ska]

There sort of is, in a couple of ways. First, off-label use. This is very common in medicine, and means drug X (or machine X) approved for Y purpose can be used for Z purpose if a physician judges it a good idea. So if a heart drug is showing promise in treating sleep apnea in early papers, your doctor could read the papers and decide it was worth a go. Or if you asked them to; trick there is they are professionally liable for it being a supportable decision. There is a form of this for compassionate use which means most of the downsides are ignored in favor of quality of life (e.g. I'm not too worried about getting you addicted to opiods if you're only going to live a few weeks).

The second way is that drugs/devices are considered against their intended use. So the argument for using more dangerous things is much easier if you are treating brain tumors than common colds. There even are fast-track (e.g. mRNA vaccine for covid) but won't be pulled out for niche uses.

What this doesn't cover is things produced in uncontrolled ways, or "i read this on the internet and want a prescription". I can see how this is frustrating for people who are willing to try anything, but I can also see the liability side.

> "When facing certain death, what's the worst that can happen? You die a bit sooner?"

Part of the problem is you certainly can make things worse, and you can make them systemically more expensive. It's one thing to say "I'm dying anyway and I want to try this" but quite another to add "and if it goes badly I expect you to try and deal with it". No easy answers, really.

[entropicdrifter]

The illegal part wouldn't be putting the chems into your body, but selling or giving such chems to someone when you know they're planning to ingest them

[tough]

It seems like a great way to allow a system that it's known to exploit desperate people to do so selling all kinds of miraculous treatments that don't have to even have a relic of science on them.

Having cancer already sucks enough, having businesses and whatnot vulturing over your condition to sell you shit that doesn't work wouldn't really make it better?

[whymauri]

This was my reaction, as well. So visually and structurally unremarkable, it's actually elegant in how 'un-exotic' it is. Love to see it!

[mrklol]

Okay, forgive me for this stupid question but my biology level isn’t that great.

But, if we know which cells to target and what their structure is, can’t we just extract some healthy cells, reproduce them, kill all cells which would dock to that pill, insert reproduced healthy cells?

So with that we don’t have to care if it attacks healthy cells, or is that reproduction idea not possible?

[fnordpiglet]

Two speculative substances, this and LK99, are both simple and cheap the synthesize. If either pan out it’s a miracle for man kind. But, it leaves me to wonder, what shenanigans will corporations go through to make it inaccessible and expensive?

[eigenvalue]

This sounds very exciting, and I liked reading your intuitive, almost tangible appreciation of the particular molecular structure. You speak of the components like they are old familiar friends! As someone who doesn't know much at all about chemistry or biology, I had what I thought was a very fascinating discussion about your comment with GPT4 which you might find cool:

https://chat.openai.com/share/28d9b203-1cb5-405b-a109-0f5042...

Basically I wanted to see if your comment, along with the detailed description of the molecular structure, could lead the AI to guess how the compound could be useful. I then proceeded to drop more and more hints and asked it to use those hints along with the structure to guess at a potential mechanism of action. In any case, it certainly helped explain to me what you were talking about!