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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: Twitter: Dereklowe

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« Chemical Biology - The Future? | Main | Avandia Goes Down: A Research Rant »

September 23, 2010

Delightful, But It Apparently Works

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Posted by Derek

And I now present today's winner of the Ugliest Molecule To Actually Show In Vivo Efficacy. Here, just in time for lunch, is Torin-1, a selective mTOR inhibitor. Yowza.

Comments (30) + TrackBacks (0) | Category: Chemical News


1. ronathan richardson on September 23, 2010 12:13 PM writes...

Finally. They've been writing papers that use that thing to prove a key point for 2 years now, with no actual structural data. Doesn't look reactive, at least. Aggregation-prone, possibly. What a strange core.

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2. d on September 23, 2010 12:14 PM writes...

It will be renamed Candlewaxin

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3. ronathan richardson on September 23, 2010 12:19 PM writes...

On second look it appears to be highly similar to NVP-BEZ235, which is less ugly and has incredible efficacy in tumor models.

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4. student on September 23, 2010 12:26 PM writes...

I have little knowledge of med chem. Can someone explain how this can be a drug since it looks like brick dust and is extremely unlikely to be water soluble?

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5. Grayscale Rainbow on September 23, 2010 12:30 PM writes...

Oh, come on Derek, fess up. You know somewhere in your career you've made a compound or two (or more) with a MW~600 and cLogP ~6, which weren't even active in vitro, much less in vivo. Most of us have but we're too ashamed to admit it, unless of course one of them is in the clinic.

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6. milkshake on September 23, 2010 12:35 PM writes...

I think this one still has some solubility left because there are no free NH in the molecule.

For another horrific example of an oral drug design, see itraconazole and posaconazole

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7. EngelGW on September 23, 2010 12:42 PM writes...

@student I don't know its solubility but the conformation of such a compound in 3D is far away as it looks like in 2D. Due to several ortho substituants, some crystal packing effects are avoided.

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8. HelicalZz on September 23, 2010 12:45 PM writes...

Some quibbles,

First the title 'Discovery of ..' makes me think natural product. But it is clear from the abstract (if not the structure), that this was 'Developed' from a scaffold, not 'Discovered'. I find use of discover in these situations to be something of an insult to the chemists.

A good definition of ugly is 'cellular IC50 = 2 nM, efficacious dose 20 mg/kg'.

To the authors credit, they propose the compound as a 'useful probe' of the mTOR pathway, not as a drug.


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9. Otis on September 23, 2010 12:48 PM writes...

I'm a nerd that I know what this could be useful for, but I don't think it'll pass through the blood/brain barrier well...

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10. Otis on September 23, 2010 1:07 PM writes...

Isn't rapamycin an Alzheimer's drug? By the same pathway, I guess it's cancer too.

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11. Bryan on September 23, 2010 1:16 PM writes...

I would bet that it has substantial off-target actions at other classes of molecular targets (GPCRs, hERG, MDR-1 and so on).

To their credit they did counter-screen 400 kinases!

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12. bfs on September 23, 2010 1:22 PM writes...

@14 - Isn't rapamycin an Alzheimer's drug?


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13. partial agonist on September 23, 2010 1:37 PM writes...

Holy Lipinski, Batman...

My chemdraw saws MW 608 and cLogP a whopping 6.2...

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14. ZZ on September 23, 2010 1:39 PM writes...

@EngeIGW - it seems to me that the 3D shape of the beast is rather remarkably limited considering its size: out of the 3 rotatable bonds that matter, two of them are co-linear and the third is practically kept parallel to them by the rigid fused triple ring system. I would venture a guess that this shape-change limitation is one of the reasons while it can be successful despite the bulky size.

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15. Mark on September 23, 2010 1:43 PM writes...

My question is, what color is it?


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16. anchor on September 23, 2010 1:54 PM writes...

#5 brick dust

on the plus side here is hoping that at the end of the day it is still an amide and that some amidase will hydrolyze (among other metabolism) to release an amine for possible conjugation and eventual elimination.

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17. BFS on September 23, 2010 2:54 PM writes...

"Posted by Derek

And I now present today's winner of the Ugliest Molecule To Actually Show In Vivo Efficacy."

To that I say caveat mTOR.

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18. andreadelsarto on September 23, 2010 6:41 PM writes...

Needs more cowbell.

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19. Jose on September 23, 2010 8:28 PM writes...

Reminds me of Praziquantel.

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20. AlchemistOrganique on September 23, 2010 9:16 PM writes...

Can anyone propose a better explanation for this compound's selectivity? It also looks like a wicked DNA/RNA intercalator.

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21. barry on September 24, 2010 12:21 AM writes...

rapamycin has been shown to have anti-cancer activity in the clinic. Because it inhibits mTOR only indirectly (and therefore blocks signalling down only one leg of the cascade) interest persists in a direct (presumably ATP-competitive) inhibitor of all mTOR activity.

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22. kristall36 on September 24, 2010 1:48 AM writes...


how do you think about Merck's mPGES-1 inhibitor?

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23. DrSnowboard on September 24, 2010 5:50 AM writes...

Black Swans of Chemistry?
I give you HCV inhibitor BMS-790052, mwt 738ish, clogP>4.5, currently going great guns in Phase2+.

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24. noname on September 24, 2010 7:21 AM writes...


HCV compounds are poor comparisons, because unlike most oral drugs, they need never leave the liver. That's why the BI, VX, and BMS compounds can be so big. Doesn't help that the target is a SOB and can only be hit be big peptidomimetics.

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25. canchem on September 24, 2010 8:08 AM writes...

BFS - funniest thing I've read in a loooong time.

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26. DrSnowboard on September 24, 2010 9:45 AM writes...

Maybe, but isn't the numbers game centred on oral absorption? I don't remember my liver being on the inside of my GI tract, but I am only a chemist. BMS cpd isn't an NS3/4 protease inhibitor either.

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27. myma on September 24, 2010 10:46 AM writes...

It looks like a hERG inhibitor to me.
and maybe a conductive paint additive too.

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28. Greg on September 24, 2010 12:43 PM writes...

Ariad's ridaforolimus is an mTOR and we will see shortly just how much that molecule has in terms of efficacy in the clinics.......

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29. barry on September 24, 2010 1:49 PM writes...

ridaforolimus inhibits mTOR only indirectly, and therefore blocks only one of two legs of signalling, just like rapamycin. We still want to know whether a direct inhibitor blocking both legs of signalling would be better for oncology.

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30. HTSguy on September 25, 2010 8:42 PM writes...

Small wonder about BMS-790052 working in vivo despite it's size, etc. It's 50pM in cellular assays!

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