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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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August 19, 2013

High Throughput Screening Services

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Posted by Derek

Here's a question that comes up once in a while in my e-mail. I've always worked for companies that are large enough to do all of their own high-throughput screening (with some exceptions for when we've tried out some technology that we don't have in-house, or not yet). But there are many smaller companies that contract out for some or all of their screening, and sometimes for some assay development as well beforehand.

So there are, naturally, plenty of third parties who will run screens for you, against their own compound collections or against something you bring them. A reader was just asking me if I had any favorites in this area myself, but I haven't had enough call to use these folks to have a useful opinion. So I think it would be worth hearing about experiences with these shops, good and bad. Keep the specific recommendations recent, if possible, but general advice and What Not to Do warnings are timeless. Any thoughts?

Comments (33) + TrackBacks (0) | Category: Drug Assays


COMMENTS

1. Anonymous on August 19, 2013 8:17 AM writes...

As long as the partner can guarantee a certain number of drug-like hits with a relevant assay at a resonable cost, then it's a no-brainer. The more they push back on this requirement, the more likely it is they are selling hot air.

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2. John Wayne on August 19, 2013 8:20 AM writes...

The first comment seems like a great question to ask if you want to find out if their BD person will lie to your face. This has to depend on what sort of screen you are performing and the breadth of their library.

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3. Anonymous on August 19, 2013 8:26 AM writes...

I think that at least for cell based cytotox screens a major reason progress is slow in this area is because they require virtually perfect implementation, which generally only comes when you have a vested interest in the actual screen. I have had some experiences in which we have transferred cell based screens to third parties for cytotox screening and they generally try to do it as quickly and cheaply as possible, and give you a bunch of BS hits that don't confirm. These things are hard enough to do that you really have to CARE about perfect implementation to achieve it. When the implementation is imperfect, they will obscure that fact, transfer some "hits" that end up being BS, take your money, and walk away to the next paying customer.

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4. Anonymous on August 19, 2013 8:26 AM writes...

@2: Obviously, I was implying that these terms should go into a contract.

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5. Teddy Z on August 19, 2013 8:32 AM writes...

This is exactly what I do for a living, but mostly in fragment space. (Think of me as Red from Shawshank Redemption "I've been known to get certain things from time to time...").
@#1. If they promise you hits, they are also lying. It all depends on the system, the library, the MOA you want hits for, and so on.
What you should be asking for is their experience in a given target class, examples they can discuss, even in general, the rationale behind their libraries, why they chose one method over another (are they method agnostic?). Will they produce the protein, curate results, etc. Are you interested in one stop shopping. It is a complex process to do it right. That's why there are experts out there.

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6. Anonymous on August 19, 2013 8:42 AM writes...

One issue is to remember to plan how to follow up hits - if you want to run an SAR internally, then you will probably need the assay internally at some point, so you need to establish if the third party will be able/willing to transfer protocols and cell lines to you (this generally depends on whether they are convinced that you will never be a fee-for-service competitor).

There will be inevitable delays while you try to reproduce assay conditions, but these will increase significantly if the assay has to be redeveloped from scratch.

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7. Anonymous on August 19, 2013 8:52 AM writes...

@5: It's not a question of "lying", but rather getting the partner to take the risk. So, if what they are selling doesn't deliver, they don't get paid. Simple.

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8. Sideline Chemist on August 19, 2013 9:48 AM writes...

The idiom "garbage in...garbage out" is completely applicable to external screening efforts (internal screening too, for that matter). I've worked at several companies that relied on external screening for starting points. Pretty much anyone can develop an assay (some companies specialize in certain target types), but if their library is composed of nothing but greasy, combinatorial-derived compounds then finding suitable drug-like starting points is not easy.

Chemical IP potential is also vital. The greatest drug-like scaffold in the world means nothing if you have to spend 3 years tinkering with it to find proprietary chemical space.

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9. Ed on August 19, 2013 9:53 AM writes...

As an addendum to this - does anyone have any insight into the above questions when applied to virtual HTS as a screening service? There are lots of suppliers listed in AssayDepot, but what sets some companies apart? what should i be asking of these providers to separate the wheat from the chaff?

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10. Anonymous on August 19, 2013 10:05 AM writes...

@9: See 7

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11. anon on August 19, 2013 11:13 AM writes...

@#1 and follow ups:
I would say your recommendations are a terrible idea.
1) any high-throughput screener who agrees to it, probably is not very experienced, and

2) high throughput screens are filled with false positives.... and your asking them to guarantee a certain number of hits? Congrats! tons of hits! any reason to think they are real? who knows!

I think your approach will lead to waste of time and effort following up hits which should have been tossed early on. Its more important to fail quickly and move on than to guarantee a certain number of hits.

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12. Anonymous on August 19, 2013 11:32 AM writes...

@11: on the contrary, if the partner has any experience they can calculate risk and price accordingly. Quality can be assured by insisting on reproducible activity in an approved assay.

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13. sgcox on August 19, 2013 11:45 AM writes...

Interesting. Are there really companies which will run HTS for you without some upfront payment ?
And on condition more hits, more money? I guess one could do this for kinases and other known "druggable" targets but not something new.

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14. Anonymous on August 19, 2013 11:51 AM writes...

@13: Not sure, but if potential partners aren't willing to take the risk based on their experience, why should any company pay them a premium while taking all the risk themselves? Otherwise they may as well do the screening inhouse, which is probably why most do. But if I'm the customer, I would only pay a premium if I can be guaranteed to get what I actually want, which is good quality hits/leads. It's up to the partners to consider how they can make that guarantee, and at what price.

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15. anon on August 19, 2013 12:30 PM writes...

@12:
your paying for the assay experience, not the guarantee of molecule binding.
Researchers can't guarantee to find a ligand for any-old protein. People have a hard enough time when its a well-defined protein with a known structure.

research results can't just be mapped out with 'risk calculation.' Anyone who says they can calculate the risk based on "its an X-class of protein" is lying to you.

why don't they take any risk? because your the only one who cares about that molecule. They offer a service. They will run it through a battery of tests. Its like saying that the durability testers for cars only get paid if the car withstands the testing, despite the fact that they have no control over the identity of the car, the materials its made from, or the quality of the manufacturing.

good luck finding someone, and all the best if you do, but it will actually make me distrust their scientists, not trust them more.

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16. Anonymous on August 19, 2013 12:37 PM writes...

@15: No, that's BS. If I'm the customer, then I'm paying to get what I actually want, which is good hits/leads, not some woolly excuse for not delivering it based on "experience".

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17. sgcox on August 19, 2013 1:08 PM writes...

There are more than one Anonymous around here I suppose, so #16:
Have you ever managed to get CRO run an assay for you (not even HTS, just an assay) without some guaranteed payment or at least a promised publication which can be used as an usefull advertisement? Just curious - will be interesting to hear the experience

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18. Anonymous on August 19, 2013 1:24 PM writes...

@17: No I haven't, we paid a CRO for screening without any such guarantee, and the quality of work was rubbish, never mind the result. So never again. Now we do all screening ourselves, or through academic collaborations, and the only way I would ever use a CRO again is if they agree to get paid only if and when they actually deliver what we want. Live and learn.

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19. sgcox on August 19, 2013 1:36 PM writes...

#18 Thanks to know it comes from the real experience, not some hypothetical situation.

May be it is indeed a reasonable approach to have CRO based on these principles. Not sure how well it might go with investors.

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20. Anonymous on August 19, 2013 1:48 PM writes...

@19: If CROs guaranteeing results is the only way they can get customers, I'm sure their investors would be quite happy to have any business at all.

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21. The Aqueous Layer on August 19, 2013 2:59 PM writes...

@18 Was the CRO you dealt with screening your compound collection, or theirs? Was the screen against a in-house target they were trying to sell, or was it a target you provided for them to screen against their compound collection?

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22. Anonymous on August 19, 2013 3:40 PM writes...

@21: it was the CRO's own "amazing" assay, based on well-established target, a library they recommended, and their "expertise". All complete crap, they couldn't even reproduce their own control experiments. They have since gone out of business, but that won't help us because we did too, thanks in part to their incompetence.

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23. Anonymous on August 19, 2013 7:35 PM writes...

Screener here. I had to work with Evotec a few years ago. Found them to be quite good for a CRO. Nothing compares to what your internal screeners can do though: they care about the end result rather than just running the screen and getting paid. Think novel assay formats & molecular mechanisms of action...

@1: I am sorry about your negative experience but I concur with others in saying hat I would be weary of a CRO "guaranteeing" hits...

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24. Anon on August 19, 2013 9:37 PM writes...

I think it's really easy to make generalizations about screening that don't apply to many scenarios. I'm not sure how many screens and what types commenters have been involved in but I've had experience with quite a few NMR fragment screening projects and it can be extremely dependent on target, exp type, library, and many other factors that should be addressed properly in a screening contract. There are high quality CROs out there.

Source: I work for a CRO that does screening

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25. Anonymous on August 20, 2013 5:21 AM writes...

@23: I fully agree that no CRO can guarantee good hits/leads, but by making payment depend on the outcome, at least they will care more about doing good quality work to find them, if there are any.

And it's not necessarily a binary option, as the work could be funded by a minimum payment to cover just the costs of screening, with a big upside "bonus" for each hit or lead that is found to meet certain quality criteria.

It just requires creative thinking to share and manage the quality and risks. :-)

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26. BioAnon on August 20, 2013 10:28 AM writes...

No one has dropped any names except for Evotec. Do people not want to share or have there just not been that many experiences with CRO shops?

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27. HTSguy on August 20, 2013 10:50 AM writes...

We had a good experience working with BioFocus.

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28. mark_cresset on August 20, 2013 11:10 AM writes...

On the virtual screening side, we've been running a virtual screening service business for more than a decade - it was Cresset's original business model before we got into software as well.

WRT @1 and @12, we used to offer a risk-sharing paradigm. Virtual screening is (and always will be) a probabilistic exercise. Sometimes you find hits, sometimes you don't - it's very highly target dependent. We used to offer an option where the client had the option of keeping their money and in return we kept the IP on the compounds. That way, if there were no hits, then it cost the client nothing, and if there were hits, it was in the client's interest to tell us and pay up :).

However, we've pretty much dropped that model. Our success rate at finding actives is pretty good (70-80%), but that still means that there were going to be 20-30% of cases where we failed to find actives - note that even a perfect virtual screening method would sometimes fail as some targets just don't have any new active compounds waiting out there in the commercially-available collections. As a result we have to charge more for the "no win, no fee" service. What we found was the vast majority of clients preferred to take the cheaper model where we are just paid for our time and the risk is theirs. The only exceptions were the people with wildly speculative programs (generally either "Can you find us a PPI inhibitor? It must obey the rule of five!", or "The assay is rather tricky, so we can only afford to screen five compounds..."), which we either had to refuse outright or put large success payments on to counter the very high risks.

Still, if people have a need for virtual screening services then give us a call, and if you absolutely require a risk-sharing agreement we can probably accommodate it unless your project is completely off the wall!

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29. Anonymous on August 20, 2013 11:22 AM writes...

We used Cresset, but none of their virtual "hits" turned out to be active, so I guess we were one of the unlucky 20-30% that paid for nothing.

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30. derek jacoby on August 20, 2013 12:42 PM writes...

Assay depot.com is an interesting service for outsourcing screening through.

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31. Steve on August 20, 2013 12:55 PM writes...

@25 As a CRO providing screening in DNA encoded libraries we (HitGen) do recognise that the deliverables in this process are molecules with confirmed activity in the relevant biological assays. For this reason we put the majority of our screening cost base into success-based milestones but there is still an upfront cost as well, thus a sharing of the "risk". I think you will struggle to find organisations who will be prepared to shoulder all the risk, since we know not all targets are going to be druggable and perhaps not all proteins provided by clients will in a be biologically relevant form.

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32. Anonymous on August 20, 2013 1:06 PM writes...

@28 & 31: Good to know there are some customer-focused CROs who are prepared to share the risks and stand by the quality output of their work. This should be standard practice.

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33. smurf on August 21, 2013 2:04 PM writes...

Both Evotec as well as BioFocus do a pretty good job. I have worked with both of them - you always have ups and downs, but all in all the experience was positive.

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