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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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In the Pipeline

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November 3, 2011

Medivation Comes Through With MDV3100

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Posted by Derek

Remember Medivation? That's the small biotech that was trying to develop a Russian compound as an Alzheimer's drug, an effort which blew up completely in early 2010. The company did have one other compound in development, targeting prostate cancer, a ligand for the androgen receptor called MDV3100.

You'll note from that link that it's a rather odd-looking compound, a thiohydantoin, which is a heterocycle that you don't see very often. The discovery of the compound is detailed here, in a collaboration between Michael Jung's group at UCLA and Charles Sawyers' at Sloan-Kettering (here's an interview with him). It's been a long road. The starting point was another known ligand, RU 59063, which comes out of research in France in the early 1990s. The whole left-hand side of MDV3100 (including the thiohydantoin) comes from that scaffold, but it behaves differently on the androgen receptor. Taking advantage of the wild and often intractable complexity of nuclear receptor signaling, it binds in a different mode than other AR ligands, and in a way that the receptor loses its ability to further bind DNA in the nucleus.

Here's the J. Med. Chem. paper (in open-access form) on the development of the series. The compounds were pushed through relatively quickly in cellular assays and in an in vivo model in mice, which allowed MDV3100 and its close analogs to stand out not only for their superior activity on the androgen receptor (which many compounds in the series had), but for their pharmacokinetics. Interestingly, the lead compound for some time seems to have been a spiro-cyclobutyl analog (RD162), but the corresponding gem-dimethyl compound was just as active and a lot easier to make, so that one became the clinical candidate.

Medivation's Phase III trial of the compound came in with data yesterday, and it was startlingly good, so much so that the trial was stopped early and the placebo group switched to the drug. The company's stock is going through the top of the chart in pre-market trading as I write, which shows that the expectations weren't all that high. But MDV3100 certainly seems to have come through, and considering how much failure we live with in drug discovery, it's nice to see something actually outperform. Congratulations to the company, and to Jung and Sawyers as well - they've added another straight-out-of-academia drug to the list, and helped to considerably advance the standard of care in prostate cancer. Good news all around.

Oh, and by the way. . .you have to wonder if this guy stuck around for this result. It all depends on what price he was in at - after today's trading, Medivation's stock might even make it up past where it was back when everyone was hoping that they had an Alzheimer's drug. Expectations!

Comments (12) + TrackBacks (0) | Category: Cancer | Clinical Trials


COMMENTS

1. John Wayne on November 3, 2011 9:42 AM writes...

This molecule is a good reminder for medicinal chemists that not all traditionally problematic function groups (hydantoins, in this example) are an issue all the time.

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2. RB Woodweird on November 3, 2011 9:47 AM writes...

Man, anytime there is a new treatment for castration-resistant prostate cancer I am strangely happy.

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3. DCRogers on November 3, 2011 11:44 AM writes...

@2 "Man, anytime there is a new treatment for castration-resistant prostate cancer I am strangely happy."

Bet doctors will feel a lot of pressure to try this drug even before seeing if castration works!

It would be tough to be a doctor and have to deliver: "Good news is, tests show your prostate cancer is castration-responsive. Bad news is, tests show your prostate cancer is castration-responsive."

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4. MLBpitcher_and_MedicinalChemist on November 3, 2011 2:29 PM writes...

Are there any PPAR agonists in the pipeline. It seems like all development in this class has stopped.

Can anyone recommend a good article to understand the complex pathways behind their signaling. Apparently, I'm not as smart as that sinkerballer with a Ph.D. from Duke in organic chemistry.

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5. -=GiMP=- on November 3, 2011 3:22 PM writes...

Can't help but remember the 'stunning' PhII results for Dimebon that encouraged Pfizer to invest heavily a few years ago... Lots of money and heartache later...squat! In a recent article on these pages 'if it looks to good to be true...'

From the horse's own mouth: http://pipeline.corante.com/archives/2010/03/03/dimebon_comes_crashing_to_earth.php

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6. Steve on November 3, 2011 3:27 PM writes...

Its useful but not a miracle cure. mean survival times increased from 13.6 to 18.4 months. While I I would welcome a few extra months, not if it in bad pain or sufffering awful side effects from the drug

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7. NoDrugsNoJobs on November 3, 2011 3:44 PM writes...

Steve - side effects from a strict androgen antagonist would be quite tolearable compared to normal cytotoxic agents. I'm not saying it would be fun to be so androgen-deprived but not as bad as many other treatments. The problem is the many patients who lose androgen-dependence in their tumor type.....

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8. Boghog on November 3, 2011 4:07 PM writes...

The critical difference for this project was a prostate cell line that was engineered to over express androgen receptor (AR) recapitulating CRPC. In ordinary prostate cell lines, the current best AR antagonist (bicalutamide) is a antagonist while an full agonist in the cell line where AR is over expressed. MCV3100 is a full antagonist in both cell lines.

In a way this project is much easier that most other nuclear receptor projects. In the metabolic field, one needs fined tuned approach to achieve the required therapeutic ratios. With CRPC, one needs a sledge hammer to completely shut down AR.

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9. David Young MD on November 4, 2011 12:16 AM writes...

That drug has a little bit of everything.... Four fluorines, a sulfa and a triple bond.

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10. gippgig on November 4, 2011 2:11 AM writes...

Make the polonohydantoin and you could do radiotherapy at the same time.

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11. Morten G on November 4, 2011 9:53 AM writes...

But will the money that a deal like this brings in for Medivation investors compensate the money spent on failures in biotech?

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12. Spence Klomp on November 8, 2011 3:20 PM writes...

Hopefully this phase 3 drug will be available to men who have not failed taxotere.

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