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.
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.
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.
"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."
“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.
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 :)
> 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?
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.
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.
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
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?
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?
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?
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:
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!
Suppressing tumor growth is how you kill cancer, is it not? Cancer cells themselves, like the original cells they mutate from, don't live forever. Depending on which type of cell we're talking about, they can die within hours (e.g. skin cells)/days (e.g. blood cells)/months (e.g. liver cells). The issue with cancer cells is they are reproducing like crazy way faster than they die, which is why the tumors grow bigger and bigger. Chemo and surgery attempt to kill or remove the tumors immediately, yes, but my understanding is that's because we have no way to stop the growth and the only hope is to eradicate them entirely before they grow too big to treat, which is why the cancer could come back if any parts are missed.
You stop the cancer cell reproduction and overall tumor growth, you also kill the cancer.
suppressing growth does not equate to 100% regression.
the growth rate could be suppressed to match the attrition rate and turn into a steady state, rather than eradication of the mutant cell lines (and their progeny).
> The affected cells show cell-cycle arrest, replication stress, apoptosis [!], and so on. And application of AOH1996 along with other known chemotherapy agents made the cells much more sensitive to those, presumably because they couldn’t deal with those on top of the problems that AOH1996 was already causing.
I guess there's nothing stopping people from just shamelessly making up data on Twitter even when they're linking the actual article. This is very cool and very promising research but "almost completely inhibits the growth of xenograft tumors without causing toxicity to experimental animals" is not the same thing as "kills 100% of tumors." I do understand that there's an incentive to lie like this on the internet - it's not just magical internet points when people get paid real money as creators for getting clicks, but come on, really? Is it worth poisoning the discussion around some actually incredibly cool and promising research while driving false hope (which can actually hurt people!) Just for a few extra pennies from twitter's creator fund?
I am a total layperson in medicine but I try to challenge myself to read Derek Lowes blog posts and comments here from people like isoprophlex who do understand it. I really appreciate the simplicity of this solution - it doesn't need to be customized for each person, it doesn't need years of work on targeting, it's stable, potentially with few side affects of users. I know even this is a long shot but if it works, the power to change society! I imagine that it would even encourage cancer screening earlier for people to make for more effective treatments.
A working treatment for many cancers will bump many more preventable forms of deaths up the charts - obesity, cars, weapons. I hope that people will be inspired to take more significant actions to reduce those when we've tackled these really really hard ones.
And due to the potential low-cost, easy administration, and storage requirements, I am reminded a bit of how antibiotics ended up working in developing countries. Doctors prescribe them for every pain, making them ineffective at best and spawning antibiotic-resistant bugs at worst. I hope the researchers are able to consider this angle (overprescription) before these medicines become a widely distributed thing in other parts of the world.
It's an exciting decade for medicine. I hope that if we don't see the efficacy we want with this one, that more "simple" formulations will come around that do work.
Infectious diseases are different because they jump from host/reservoir to host/reservoir and can take their "experience" with them. Cancers spawn off from normal cells that mutate randomly. So the general scheme is that cancers (and each person's cancer's drug-resistance) develops from scratch in isolation within each person. Basically there's no real mechanism for one person's cancer to translate/share its experience against drugs with another person's cancer. Some cancers are related to viruses by increasing mutation rates which in turn increases the chance of a cancer developing. So basically I wouldn't expect overprescription to produce drug-resistance the way it can for anti-virals and anti-bacterials.
It seems to be getting more popular here to link to a twitter blurb, which links to the actual article. In this case, the blurb adds zero to the discussion, if anything adding blatant misinformation.
Readit News
A New Mode of Cancer Treatment - https://news.ycombinator.com/item?id=36982813 - Aug 2023 (205 comments)
New targeted chemotherapy able to kill all solid tumors in preclinical research - https://news.ycombinator.com/item?id=36978199 - Aug 2023 (32 comments)
'Cancer-killing pill' is now being tested on humans - https://news.ycombinator.com/item?id=36969500 - Aug 2023 (33 comments)
Cancer pill AOH1996 shows promise in annihilating all solid tumours - https://news.ycombinator.com/item?id=36960895 - Aug 2023 (19 comments)
Cancer pill AOH1996 shows promise in annihilating all solid tumours - https://news.ycombinator.com/item?id=36960292 - Aug 2023 (16 comments)
Edit: @dang: Thanks, incorporated your addition.
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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.
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
I first thought it was a joke because of the two "HN" bonds hah, pardon me.
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...
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.
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"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...
“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.
I much prefer your description of the molecule than the one found on its Wikipedia page.
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?
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.
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?
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?
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!
From the article in Cell:
"Given orally, AOH1996 suppresses tumor growth but causes no discernable side effect" is a VERY different result.
You stop the cancer cell reproduction and overall tumor growth, you also kill the cancer.
the growth rate could be suppressed to match the attrition rate and turn into a steady state, rather than eradication of the mutant cell lines (and their progeny).
https://www.science.org/content/blog-post/new-mode-cancer-tr...
Named after a girl that died. Resulted in fundraising for Neuroblastoma, and this medicine.
A working treatment for many cancers will bump many more preventable forms of deaths up the charts - obesity, cars, weapons. I hope that people will be inspired to take more significant actions to reduce those when we've tackled these really really hard ones.
And due to the potential low-cost, easy administration, and storage requirements, I am reminded a bit of how antibiotics ended up working in developing countries. Doctors prescribe them for every pain, making them ineffective at best and spawning antibiotic-resistant bugs at worst. I hope the researchers are able to consider this angle (overprescription) before these medicines become a widely distributed thing in other parts of the world.
It's an exciting decade for medicine. I hope that if we don't see the efficacy we want with this one, that more "simple" formulations will come around that do work.
Or read Derek Lowe's response on AOH1996:
https://www.science.org/content/blog-post/new-mode-cancer-tr...
Or read about the drug that came before it, but didn't metabolize well:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6279569/
Or read about other new, interesting anti-cancer drugs:
https://med.stanford.edu/cancer/about/news/rewiring-cancer-c...
https://www.nature.com/articles/s41586-023-06348-2
We need some good news these days.
This is the actual article:
https://www.cell.com/cell-chemical-biology/pdfExtended/S2451...
I recommend replacing the link and the title with what appears on the Cell website.
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