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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: Twitter: Dereklowe

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June 29, 2009

Eli Lilly Gives It Away

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Posted by Derek

Not long ago, I wrote about a Pfizer program for smaller companies to come screen their targets against Pfizer's compound bank. Now Eli Lilly has flipped that around. In an initiative to bring other people's compounds out of the stockrooms and off the shelves, they'll screen them for free.

These aren't single-target assays. The company has four phenotypic screens going (for Alzheimer's, diabetes, cancer, and osteoporosis) and will look for improvement by any mechanism that comes to hand. No chemical structure information is shown to Lilly (I assume that they just know the molecular weight so they can run a dilution series). If something looks interesting, the company and the owners of the chemical matter have 120 days to come to terms for any further development deal - if not, then all rights revert to the submitter, and they can publish the data from the screens.

Lilly's working out a universal material transfer agreement, in collaboration with a number of universities, so that the paperwork stays the same every time. That's a good move. The lawyering can be a real holdup - in my experience, every party in these agreements usually comes in with slightly different wording in their magic legal spells, requiring several rounds of reconciliation before everyone's ready to sign.

I think that this is a worthwhile idea, and that they'll get a lot of takers. There are plenty of compounds sitting around in academic labs gathering dust, so why not send 'em in? The worst that can happen is nothing, and the best is that the compound actually turns out to be worth something. But will anything come out of it? The closest program to this is surely the National Cancer Institute's long-standing (since 1990) NCI-60 screening program, which also runs at no cost to the submitters. Even so, a recent reference mentions that there are between 40,000 and 50,000 compound in the NCI database, which actually seems rather small, considering. (To be fair, the program is not being funded at the levels that it was during the early 1990s). The only marketed compound that I'm aware of that can be said to have come out of the NCI-60 screen is Velcade (bortezomib), known then as PS-341, which was sent in for screening by Proscript Pharmaceuticals in the mid-1990s. Many other interesting structures have turned up along the way, though, which for various reasons haven't made it all the way through.

It'll be quite interesting to see what sort of hit rate Lilly's phenotypic assays call up - I hope they tell us. I have a lot of sympathy for the mechanism-agnostic approach myself, and I'd like to see how closely my bias are aligned to reality.

Comments (18) + TrackBacks (0) | Category: Drug Assays | Drug Development


1. Sili on June 29, 2009 9:05 AM writes...

Do you think they'll be able to withstand the temptation to analyse the hits? It wouldn't take much time with nmr and ms to figure out what's in the vials.

Of course, the minute word gets out, the scheme is dead, but if the prize a billion dollar drug, will they care?

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2. Mark on June 29, 2009 9:10 AM writes...

Merck was doing this back when I was in grad school (late 90s). Every previous unknown compound our group made, Merck would give us $100.

I have no idea what the agreement was in terms of rights to develop, but it was a good way for Merck to get new compounds.

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3. DrZZ on June 29, 2009 9:15 AM writes...

The 40-50K for the NCI screen refers to the number of compounds whose results are publicly available. The total number is a bit more than double that. In the 1990s the capacity was about 15K per year (remember these are 5 concentrations against 60 tumor cell lines) and there was a contract that actively solicited submissions. The current capacity is about 2-3K new compounds per year and there is no active solicitations.

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4. Ed on June 29, 2009 10:06 AM writes...

How long is the NCI backlog though?

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5. Jose on June 29, 2009 10:19 AM writes...

My first though was identical to Sili's. HRMS, 13C and a proton, and hammer out a novel, related series, and you are off to IPO. So what if they screw over a teeny biotech, or get their IP for a song- either way they win. Smart, that. Desperate, too.

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6. Daniel Haszard on June 29, 2009 10:22 AM writes...

Eli Lilly has been around for a century,and a proven performer.I am waiting to see how they resolve the costly Zyprexa saga.

Daniel Haszard

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7. anon the II on June 29, 2009 10:37 AM writes...

I'm confused here. My understanding was that one would submit the structure of a compound that he/she had lying around the lab and Lilly would run it through their virtual screens. If something looked good, then, you would submit an actual sample. The structure would be known up front and there would be no liquids used in the first pass.

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8. anon the II on June 29, 2009 10:49 AM writes...

Oh, I see, maybe. This link is more definitive than the original of a couple of weeks ago.

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9. You're Pfizered on June 29, 2009 10:52 AM writes...

7-You are correct. The link states:

"After a university has joined the program, researchers there who want to submit a compound for testing would first enter its chemical structure into a web portal."

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10. CMCguy on June 29, 2009 11:06 AM writes...

In the past I believe there was some hesitancy by most of industry to submit compounds to the NCI for screening because of certain IP and "claw back" concerns regarding NIH policies and also the "slow response cycles" encountered. Not sure how it is today relative to those issues but would guess most companies have internal or contract out cancer screening analogous to NCI lines so data is faster and less entangled.

Like #2 Mark I recall in 80s "selling compounds" from our lab to both Pharmas and Agros to fund the purchase lab equipment. Know nothing of the follow-on arrangements if discovered a hit.

Would Lilly (or any screen) need the MW or just the concentration if supplied as solutions? I know some debate on preferred solvents, i.e. DMSO, plus I would worry about most (org syn) grad students solution preps so guess having solids desirable.

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11. anon on June 29, 2009 12:35 PM writes...

I don't understand how chemical space can be meaningfully parsed based on parameters which are inadequate to rebuild the (blinded) structure.

Mechanism agnostic approaches should be reserved for areas in which we know very, very little about the mechanism, i.e. not the areas Lilly is proposing screens.

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12. Igor on June 29, 2009 12:48 PM writes...

Concerning the comments about the temptation to determine the structure of the compound, I refer everyone to the actual MTA, which is available on the Lilly program's website.

They address this several places, including a section on the security of the structure submission and a statement that they won't try to determine the structure.

As Derek mentions, this is a well put together general MTA which should work well for most academic institutions looking for nuggets in their work, however I doubt any experienced, sophisticated academic or small biotech organization is going to be able to use this without some additional attorney work.

Maybe I've been around too long, but I can see a couple of places Lilly could sneak around the MTA and legally take advantage of the situation.

Nonetheless, it's still an interesting program and well worth our best wishes that it reaps additional successes. I hope other companies put similar programs into place, albeit with different endpoints.

Additional details regarding the structure:
- The structure is submitted online and is processed by a dedicated and secure server outside the Lilly internal servers and with very limited access.
- The structure is converted computationally into a fingerprint file (doesn't say Daylight, MDL, MOE, or which algorithm) which scores it good, bad or ugly.
- The sample that is sent gets an LC/MS, and they specify this is only for verifying purity.
- There is a line that states that no Lilly scientist will attempt to determine the structure.

Nonetheless, I think caveat emptor still applies here.

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13. Sili on June 29, 2009 1:35 PM writes...

Thank you, Igor.

So at least the appearance of popriety is in place.

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14. David on June 29, 2009 3:08 PM writes...

the Anticonvulsant Screening Program has been running with great success since the 70's.

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15. madeit on June 29, 2009 7:53 PM writes...

Wow, you mean I can screen all your combichem crap

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16. befuddled on June 30, 2009 6:12 AM writes...

#11 anon:

I assume the chemical fingerprint used to identify the structure will be similar to a digital fingerprint ( In that case, it's merely a identifier which is not (practically) able to be used to reconstruct the original data.

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17. partial agonist on June 30, 2009 9:02 AM writes...

I think that the point of the fingerprint is to establish a progile for the compound (size, shape, log P, solubility, arrangement of donors and acceptors) and then they will determine if very similar compounds have already been screened, in what assays. and what were the results. Then the compounds can be prioritized (novel = high priority) and even the appropriate assays can be recommended.

I had some discussions last year with screening some compounds I had made and suspected some activity but lacked the wherewithal (funding) to set up all the bio creens. A person I know at Lilly siggested I contact their IT group and they could "fingerprint" my compounds and that Lilly may have interest if they scored differently than things already in their deck. I didn't follow though at the time.

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18. John Lamb on July 5, 2009 3:56 PM writes...

I am amazed that people still talk about the NCI 60 cell line screen - they (the NCI) published a paper showing that there is essentially no predictive value of this for their xenograft assays or for efficacy in the clinic. Also others have shown that the assay used Sulphorhodamine B), doesn't measure cell killing.

If something demonstrably does not work, why continue using it? All it does is create a ndistraction.

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