6 ms·

https://en.m.wikipedia.org/wiki/AOH1996 https://en.m.wikipedia.org/wiki/AOH1996 Look at that molecular structure. Incredible. Two amide bonds, a completely un

https://en.m.wikipedia.org/wiki/AOH1996 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_ 3y ago
> 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 https://www.youtube.com/watch?v=cISYzA36-ZY
- janejeon 3y ago
  Now let's see Paul Allen's molecule.
- deep_merge 3y ago
  *American Psycho. Dude in Psycho didn’t use a business card.
- nine_k 3y ago
  Only it's the inverse: no subtlety, no surprises, all plain.
  - Terr_ 3y ago
    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.)
tigerlily 3y ago
> 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 3y ago
  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 :)
teruakohatu 3y ago
Can you explain to a layman why works to kill tumors and not healthy cells?
- isoprophlex 3y ago
  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_antigen https://en.m.wikipedia.org/wiki/Proliferating_cell_nuclear_a...
  - mbreese 3y ago
    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.
    - pulse7 3y ago
      It is written "no discernible side effects"... So we will see...
    - 7moritz7 3y ago
      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
plibither8 3y ago
> Look at that molecular structure. Incredible. I first thought it was a joke because of the two "HN" bonds hah, pardon me.
kybernetikos 3y ago
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-treatment https://www.science.org/content/blog-post/new-mode-cancer-tr...
- BenFranklin100 3y ago
  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.
  - szundi 3y ago
    Goal is to die for some other reason before cancer evades this
  - solomatov 3y ago
    >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).
  - larkost 3y ago
    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.
ncann 3y ago
> 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?
- thatguy0900 3y ago
  The worst that can happen is a industry springing up around giving terminally ill scared desperate people suger pills at a 10000% markup
- entropicdrifter 3y ago
  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 3y ago
  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?
- adebiase44 3y ago
  There is compassionate use: https://www.cancer.org/cancer/managing-cancer/making-treatment-decisions/clinical-trials/compassionate-drug-use.html#:~:text=Compassionate%20drug%20use%20means%20making,FDA)%20are%20called%20investigational%20drugs https://www.cancer.org/cancer/managing-cancer/making-treatme....
- ska 3y ago
  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.
eigenvalue 3y ago
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-a109-0f5042e34a95 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!
whymauri 3y ago
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 3y ago
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 3y ago
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?

Terr_ 3y ago

> 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 https://www.youtube.com/watch?v=cISYzA36-ZY

janejeon 3y ago
Now let's see Paul Allen's molecule.
deep_merge 3y ago
*American Psycho. Dude in Psycho didn’t use a business card.
nine_k 3y ago
Only it's the inverse: no subtlety, no surprises, all plain.
- Terr_ 3y ago
  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.)

tigerlily 3y ago

> 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 3y ago
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 :)

teruakohatu 3y ago

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

isoprophlex 3y ago
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_antigen https://en.m.wikipedia.org/wiki/Proliferating_cell_nuclear_a...
- mbreese 3y ago
  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.
  - pulse7 3y ago
    It is written "no discernible side effects"... So we will see...
  - 7moritz7 3y ago
    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

plibither8 3y ago

> Look at that molecular structure. Incredible. I first thought it was a joke because of the two "HN" bonds hah, pardon me.

kybernetikos 3y ago

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

BenFranklin100 3y ago
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.
- szundi 3y ago
  Goal is to die for some other reason before cancer evades this
- solomatov 3y ago
  >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).
- larkost 3y ago
  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.

ncann 3y ago

> 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?

thatguy0900 3y ago
The worst that can happen is a industry springing up around giving terminally ill scared desperate people suger pills at a 10000% markup
entropicdrifter 3y ago
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 3y ago
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?
adebiase44 3y ago
There is compassionate use: https://www.cancer.org/cancer/managing-cancer/making-treatment-decisions/clinical-trials/compassionate-drug-use.html#:~:text=Compassionate%20drug%20use%20means%20making,FDA)%20are%20called%20investigational%20drugs https://www.cancer.org/cancer/managing-cancer/making-treatme....
ska 3y ago
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.

eigenvalue 3y ago

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-a109-0f5042e34a95 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!

whymauri 3y ago

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 3y ago

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 3y ago

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?