hckrnws

This article kind of grinds my gears. I feel like there is an unstated assumption that people in pharma R&D are idiots and haven’t thought of this stuff.

Pharma companies care very much about off target effects. Molecules get screened against tox targets, and a bad tox readout can be a death sentence for an entire program. And you need to look at the toxicity of major metabolites too.

One of the major value propositions of non small molecule modalities like biologics is specificity, and alternative metabolism pathways; no need to worry about the CYPs.

Another thing they fail to account for is volume of distribution. Does it matter if it hits some receptor only expressed in microglia if it can’t cross the blood brain barrier?

Also the reason why off targets for a lot of FDA approved drugs are unknown is because they were approved in the steampunk industrial era.

To me this whole article reads like an advertisement for a screening assay.

I work in drug discovery (like for real, I have a DC under my belt, not hypothetical AI protein generation blah blah) and had the opposite experience reading it. We understand so little about most drugs. Dialing out selectivity for a closely related protein was one of the most fun and eye opening experiences of my career.

Of course we've thought of all these things. But it's typically fragmented, and oftentimes out of scope. One of the hardest parts of any R&D project is honestly just doing a literature search to the point of exhaustion.

I side with you. The more you know, the more you discover what you don’t know.

Every attempt to consider the extremely complex dynamics of human biology as a pure state machine, like with Pascal, deterministic of your know all the factors, is simplification and can safely be rejected as hypotheses.

Hormons, age, sex, weight, food, aging, sun, environmental, epigenetic changes, body composition, activity level, infections, medication all play a role, even galenic.

>molecules get screened against tox targets

sure! i cover this in the essay, the purpose of this dataset is not just toxicity, but repurposing also

>toxicity of major metabolites

this is planned (and also explicitly mentioned in the article)

>no need to worry about CYP’s

again, this is about more than just toxicity

>volume of distribution

i suppose, but this feels like a strange point to raise. this dataset doesnt account for a lot of things, no biological dataset does

>advertisement

to some degree: it is! but it is also one that is free for academic usage and the only one of its kind accessible to smaller biopharmas

My main point of skepticism about repurposing is whether this is giving any of new and actionable information. It seems to be reliant on pre existing target annotations, and qualified targets already have molecules designed for them. Is the off-target effect strong enough to give you a superior molecule? Why not just start by picking a qualified target and committing to designing a better molecule without doing all the off target assay stuff first?

Interestingly, it does not seem to have any controlled substances - even Schedule V drugs like Lyrica (pregabalin). So they've mapped estradiol and estrone, but not testosterone or drostanolone. Also cabergoline and pramipexole, but not amphetamine or methylphenidate.

Is testosterone a controlled substance? But why?

Taking extra testosterone can be acutely rewarding and stimulating. It has moderate addiction potential.

It also creates physical dependence by suppressing your body’s production, resulting in testicular atrophy. Some people who experiment with testosterone discover that it can take months or years to rebound, if they can at all.

All steroids have a very high risk of misuse, it's incredibly easy to get your body addicted one way or another and it's one of those things that's very hard to fix after the fact.

Steroid abuse indicates body dysmorphia. There isn’t an addictive property like other abused drugs, unless you’re considering it addictive via its effects on dopamine production.

Your body doesn’t become addicted, though. The potential for harm is real if you are not taking it under medical supervision or without proper knowledge of usage, like any other drugs.

This is incorrect. Even steroid creams you use externally for exzema and such are addictive to the point where there's a whole ramp on and ramp off procedure when you get prescribed. Your body will permanently down regulate producing the compound if you're not careful. Steroids are a much wider group of compounds than just testosterone, and your body uses them for a whole host of things.

> There isn’t an addictive property like other abused drugs,

This is incorrect. Testosterone can be acutely rewarding and reinforcing, especially at high doses used by people seeking these effects.

Seeking testosterone does not indicate body dysmorphia. People want it (or think they want it) for numerous reasons, from getting stronger to feeling “alpha” to thinking it will give them an edge.

It’s also very dependence inducing because it shuts down physical production, so the person needs to continue taking it just to get back to baseline after using it for a while. At my very first job one of my coworkers got ahold of some testosterone gel and used it for several months until he ran out and couldn’t get any more. I clearly remember how bad he felt while going through withdrawals and rebound for months. I left before he fully recovered.

This is really not true. When speaking of high dose testosterone you mean steroids, so that is the term I will use. And steroids mess people up badly. Severe anxiety, poor sleep, mental fog, and then countless effects on your organs and other factors. And as there tend to be drugs taken to reduce the side effects of other drugs you end up taking an obscene amount of drugs, and still suffering side effects.

There's a reason pro body builders generally do not ever recommend them unless somebody is going to compete, where it's a practical necessity. Obviously people can get psychologically addicted to the effects - high energy, easy physique gains, and so on. And when one gets off steroids not only will these generally greatly diminish, but there's a very high probability of one becoming simply fat if they don't dramatically shift their lifestyle. And so that can make it very difficult for people to quit, but they do - because steroids aren't what most people think.

I live in a country where you can legally buy steroids OTC for really cheap - less than $20/month for genuine pharmaceutical steroids. And you can see at the gym a lot of guys have tried this out, and quit, because you wear it for life. They'll be 'huge' but very soft/flabby after quitting the steroids.

The addictive component makes sense, does that mean men who are injured and produce less go through withdrawal? Or like men as they age? That sounds miserable.

It means the body stops producing it and won't ever again.

This is absolutely false. There's thousands of gym bros who've done absolutely stupid cycles with absolutely no post cycle therapy who've recovered and are producing testosterone again.

That's the tag-line but it isn't true.

I personally know of several early 20s guys who were between light and heavy cycles all under the supervision of doctors (or at least getting blood tested periodically).

All of them have renal issues, kidney issues, adrenal system issues, thyroid issues. Some have heart problems. Not one of them is unscathed.

Because it can be dangerous if misused.

It's a steroid, so body builders would use it constantly. It's a sex hormone, so people would use it to masculinize themselves and amp up their sex drive, and it's part of the pubertal cycle so children exposed to it pre-puberty can have masculinizing pubertal side effects before their actual puberty starts.

Everything can be dangerous if misused

I'm not saying to sell it over the counter but surely just bring a prescription would be sufficient. I see medspa clinics advertising it to men for its masculinizing effects so it can't be that hard to acquire.

You asked why it was a controlled substance.

It's not hard to acquire. Doesn't mean that it's not a controlled substance.

And in fact it is sold over the counter in other countries like Mexico. You get a "prescription" from the "on-site pharmacist" who is actually just some person who works the register.

Is that how that works?! I've always wondered what legal trickery they used since Mexico isn't listed on the WHO's list of countries who don't require Rx for antibiotics.

Wouldn't needing a prescription be... a control?

Yes, but the DEA is unrelentingly cranky and likes to tell physicians how to practice medicine despite swearing up and down that they would never, ever do that.

California used to have a medical marijuana program where access was supposed to be controlled by requiring licensed physicians to prescribe it. Turns out there's enough disgraced doctors to rubber stamp huge volumes of prescriptions, rendering the control a joke.

If the DEA isn't cranky, we go back to pill mills.

People have been doing this for literally decades. Check out work by Tattonetti

EvE Bio dataset and explorer: https://data.evebio.org/

Novartis dataset paper: https://doi.org/10.1038/s41467-023-40064-9

This substack has a serious fraud smell