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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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February 1, 2013

So How Does One Grow Beta-Cells?

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Posted by Derek

The short answer is "by looking for compounds that grow beta cells". That's the subject of this paper, a collaboration between Peter Schulz's group, the Novartis GNF. Schultz's group has already published on cell-based phenotypic screens in this area, where they're looking for compounds that could be useful in restoring islet function in patient with Type I diabetes.

These studies have used a rat beta-cell line (R7T1) that can be cultured, and they do good ol' phenotypic screening to look for compounds that induce proliferation (while not inducing it across the board in other cell types, of course). I'm a big fan of such approaches, but this is a good time to mention their limitations. You'll notice a couple of key words in that first sentence, namely "rat" and "cultured". Rat cells are not human cells, and cell lines that can be grown in vitro are not like primary cells from a living organism, either. If you base your entire approach this way, you run the risk of finding compounds that will, well, only work on rat cells in a dish. The key is to shift to the real thing as quickly as possible, to validate the whole idea.

That's what this paper does. The team has also developed an assay with primary human beta cells (which must be rather difficult to obtain), which are dispersed and plated. The tricky part seems to be keeping the plates from filling up with fibroblast cells, which are rather like the weeds of the cell culture world. In this case, their new lead compound (a rather leggy beast called WS-6) induced proliferation of both rat and human cells.

They took it on to an even more real-world system, mice that had been engineered to have a switchable defect in their own beta cells. Turning these animals diabetic, followed by treatment with the identified molecule (5 mpk, every other day), showed that it significantly lowered glucose levels compared to controls. And biopsies showed significantly increases beta-cell mass in the treated animals - all together, about as stringent a test as you can come up with in Type I studies.

So how does WS6 accomplish this? The paper goes further into affinity experiments with a biotinylated version of the molecule, which pulled down both the kinase IKK-epsilon and another target, Erb3 binding protein-1 (EBP1). An IKK inhibitor had no effect in the cell assay, interestingly, while siRNA experiments for EBP1 showed that knocking it down could induce proliferation. Doing both at the same time, though, had the most robust effect of all. The connection looks pretty solid.

Now, is WS6 a drug? Not at all - here's the conclusion of the paper:

In summary, we have identified a novel small molecule capable of inducing proliferation of pancreatic β cells. WS6 is among a few agents reported to cause proliferation of β cells in vitro or in vivo. While the extensive medicinal chemistry that would be required to improve the selectivity, efficacy, and tolerability of WS6 is beyond the scope of this work, further optimization of WS6 may lead to an agent capable of promoting β cell regeneration that could ultimately be a key component of combinatorial therapy for this complex disease.

Exactly so. This is excellent, high-quality academic research, and just the sort of thing I love to see. It tells us useful, actionable things that we didn't know about an important disease area, and it opens the door for a real drug discovery effort. You can't ask for more than that.

Comments (18) + TrackBacks (0) | Category: Chemical Biology | Diabetes and Obesity | Drug Assays


COMMENTS

1. ptm on February 1, 2013 10:35 AM writes...

That's great news.

One thing makes me wonder though, it seems like a rather straightforward approach, one that any company aiming to treat diabetes should attempt. So why hasn't it been done before?

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2. David Formerly Known as a Chemist on February 1, 2013 10:55 AM writes...

And better yet, the compound they identified actually looks like an attractive lead-like molecule rather than the polyhydroxylated planar aromatic systems you typically see come out of academic labs. Bravo!

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3. Boghog on February 1, 2013 11:36 AM writes...

Nice example of phenotypic screening identifying an agent with synergistic polypharmacology.

Further support that IKK-epsilon is a relevant target: IKK-epsilon knockout mice are protected from diet-induced insulin resistance (PubMed: 19737522).

Inhibiting the other target (EBP1/PA2G4) however is a bit worrying since it is may act as a tumor suppressor, but at the same time makes sense if one is trying to stimulate cell growth.

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4. Kent G. Budge on February 1, 2013 12:12 PM writes...

"So How Does One Grow Beta-Cells?"

Put a male and female betta in the same tank, and hope they decide to mate rather than kill each other?

Jokes aside, this is great stuff.

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5. NJBiologist on February 1, 2013 12:36 PM writes...

@1 PTM: "So why hasn't it been done before?"

Possibly because Type 2 is the growth market, not Type 1? That's not a great reason on several levels (Type 1 is important, there's still a use for beta cell-sparing therapies in Type 2, etc.), but I can easily imagine this question coming from corporate leadership.

Possibly because there are already therapies that are at least beta cell-sparing (DPP-4 inhibitors and incretins; possibly some kinds of dietary fiber)?

That's a devil's advocate response; I think this is a great thing.

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6. TeddyZ on February 1, 2013 3:12 PM writes...

So, this is GNF. What about the 100 million Merck dropped on him?

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7. Chemist For Life on February 1, 2013 4:27 PM writes...

WS-6 is a kind of hybrid of the known kinase inhibitors sorafenib and imatinib. I'm sure WS-6 hits more kinases than one would like, but appropriate optimization (dialing out such activity) is certainly possible.

One question I have is regarding the biotinylated WS-9.

Once you start placing large groups like that off of a given small-molecule, it can often lead to interference with respect to binding with certain targets (one has essentially changed the original structure dramatically). Of course, in the kinase field, biotinylated derivatives have been used in large panel screening technology, however the linker typically is placed such that binding affinity with kinases is maintained.

What was the rationale behind placing the linker off of the piperazine moiety? Did they also try linking off of the right hand pyrimidine amide..?


In each case, maybe one arrives with a different set of binding partners?

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8. Toad on February 1, 2013 5:01 PM writes...

Derek,
Just a picky item. In the future, it may help the audience of non-discovery folks to use mg/kg instead of mpk. Writing the units makes sense for the readers with broad backgrounds, without having to look it up. Feel free to use it around the lab in speech (I do), but I would refrain from the acronym in written form.

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9. interested reader on February 1, 2013 5:11 PM writes...

To point out just one of the many problems with this paper, the authors state that they "observed ~50% increase in beta-cell mass in WS6-treated mice (Figure 4B, right panel)." However, if one looks at the right panel of Figure 4B, they indicate that the difference in beta-cell mass is n.s. (not significant). Thus, the decrease in blood glucose occurs despite a non-significant increase in beta-cell mass. How odd.

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10. sgcox on February 1, 2013 5:12 PM writes...

Well, this is exactly where imatinib/sorafenib/someothernib is protruded into solution. There is no doubts authors know very well the WS-6 looks like a typical TK inhibitor and simply wanted to see which one by placing biotin at the obvious linker place. Instead they puled out unrelated proteins. Very interesting paper indeed !

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11. watcher on February 1, 2013 7:23 PM writes...

Juat the type of work I'd expect from Peter Schultz, and nothing less in terms of quality and value

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12. KinaGuy on February 1, 2013 8:50 PM writes...

It's a cool paper, but the SI is seriously lacking. The abstract mentions kinome profiling. Where are those results? No way that compound is selective.

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13. Anonymous BMS Researcher on February 2, 2013 8:01 AM writes...

@Toad: good point. Actually the pronunciation I hear most often in Working Group meetings is "miggs per kigg," and I'm old enough to remember the Cold War when talking heads on TV worried about how well our latest fighter planes could compete with the latest Soviet MIG fighter planes...

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14. Anonymous BMS Researcher on February 2, 2013 8:02 AM writes...

@Toad: good point. Actually the pronunciation I hear most often in Working Group meetings is "miggs per kigg," and I'm old enough to remember the Cold War when talking heads on TV worried about how well our latest fighter planes could compete with the latest Soviet MIG fighter planes...

Permalink to Comment

15. Devices R Us on February 2, 2013 1:49 PM writes...

One problem with doing this for T1 diabetes is that simply growing or replacing beta cells does not stop the autoimmune attack on the new cells. You not only need new cells but you need to put them somewhere that can isolate them from the immune system. Getting human beta cells is not hard; there are tons of pancreas transplants every year and quite a few pancreatectomies as well. See Camillo Ricordi's work for a sense of the complexity of beta cell replacement therapies. For T2 diabetes, I think that even with the DPPIV inhibitors there is quite a bit of room for improvement.

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16. Chemboy on February 2, 2013 10:37 PM writes...

Without reading the paper I can safely say it's just another crap from his group. Don't even waste you time and clean thoughts on it.

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17. Mike on February 3, 2013 3:31 PM writes...

Without reading the paper I can safely say that it's GREAT! Another triumph by Schulz and the gang. A++++ would fund grant again.

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18. Betamax on February 4, 2013 9:51 PM writes...

Devices, I agree that immune attack is still a potential problem, but these kinds of compounds can at least help answer how much of a problem. Combination therapy with an immunomodulator could be a future approach, too.

Two big challenges with this approach: 1) increasing beta-cell proliferation specifically, and 2) correlating rodent and human beta-cell effects, which are notoriously dissimilar in ability to proliferate. Their data look promising, though.

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