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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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June 25, 2012

A Kinase Inhibitor Learns Something New

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Posted by Derek

Here's another reminder that we don't know what a lot of existing drugs are doing on the side. This paper reports that the kinase inhibitor Nexavar (sorafenib) is actually a pretty good ligand at 5-HT (serotinergic) receptors, which is not something that you'd have guessed at all.

The authors worked up a binding model for the 5-HT2a receptor and ran through lists of known drugs. Sorafenib was flagged, and was (experimentally) a 2 micromolar antagonist. As it turns out, though, it's an even strong ligand for 5-HT2b (57 nM!) and 5-HT2c (417 nM), with weaker activity on a few other subtypes. This makes a person wonder about the other amine GPCR receptors, since there's often some cross-reactivity with small molecule ligands. (Those, though, often have good basic tertiary amines in them, carrying a positive charge under in vivo conditions. Sorafenib lacks any such thing, so it'll be interesting to see the results of further testing). It's also worth wondering if these serotinergic activities help or hurt the drug in oncology indications. In case you're wondering, the compound does get into the brain, although it's significantly effluxed by the BCRP transporter.

What I also find interesting is that this doesn't seem to have been picked up by some of the recent reports on attempts to predict and data-mine potential side effects. We still have a lot to learn, in case anyone had any doubts.

Comments (18) + TrackBacks (0) | Category: Cancer | Drug Assays | The Central Nervous System | Toxicology


1. luysii on June 25, 2012 10:41 AM writes...

Along the lines of we don't know all the things our drugs are doing, how about a tricyclic antidepressant improving the function of CFTR, the protein defective in cystic fibrosis. Binding of amitryptyline to the reuptake protein for amine neurotransmitters has been well studied on many levels (including the molecular). What's it doing to CFTR?

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2. Curious Wavefunction on June 25, 2012 11:54 AM writes...

Seriously though, I wonder if this should be all that surprising. These drugs are entities that have never been encountered by evolution before, and therefore evolution never had a chance to tune out binding between them and random proteins. At the same time they share some similarities with natural molecules. What are the chances that a small molecule never encountered by evolution before will bind exclusively to one among tens of thousands of proteins built from the same twenty amino acids? In any case, from a scientific perspective it's of course fascinating to analyze all these cross reactions.

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3. Biotechtranslated on June 25, 2012 12:29 PM writes...

This is pretty rough overview and assumes that Nexavar acts as an antagonist at each receptor.

5-HT2a antagonist - antipsychotic
5-HT2b antagonist - anti-migraine/anti-platelet, known cardiotoxicity issues
5-HT2c antagonist - questionable antidepressant effects

Looking at the potency, its seems like 5-HT2b is the one that should stick out.

Any known cardiotoxicity issues with Nexavar? Particularly heart-value issues?


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4. jvn on June 25, 2012 2:39 PM writes...

Here is an article that comes to mind when I read about the side effects of sorafenib:
Hypertension and diarrhea ought to be explained fairly well by an interaction of sorafenib with 5-HT2B receptors in cardiac tissue and gut.

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5. Imaging guy on June 25, 2012 3:35 PM writes...

I wonder whether it would be possible make a small molecule drug which only binds to a protein. When you are checking binding properties of drugs, you can only test against a small percentage of known proteins and so far we have experimental evidence at protein level only in 60% of 20000 protein coding genes. Once drugs reach into systemic circulation they can bind to proteins other than its intended one and even to DNA, RNA and metabolites (so far nearly 8000 identified in human body). Parameter free approach (when you make no assumption about potential targets of your drug) using pull down approach and mass spectrometry identification might alleviate this problem.One group identifies the target of thalidomide drug using this method. "Identification of a Primary Target of
Thalidomide Teratogenicity". However I heard that this method is quite difficult.

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6. luysii on June 25, 2012 4:04 PM writes...

#2: Excellent point, consider how two seven transmembrane G protein coupled receptors (GPCRs) distinguish between dopamine and norepinephrine, differing only by a hydroxyl group on the beta carbon. Both have been around for a long time evolutionarily.

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7. Twelve on June 25, 2012 5:04 PM writes...

Are you guys serious?? This isn't a discussion about how hard it is to distinguish between different proteins - that's why God created Panlabs and Cerep. If you want to put a clean candidate into development, all you have to do is do the routine broad screens. Those 5HT receptors are all on the commercially available list...either the jokers running the program knew these off-targets were lighting up and didn't care, or they decided to save a few bucks and pretended that kinase inhibitors don't need non-kinase counterscreens. Either way, amateur hour all the way around.

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8. pete on June 25, 2012 6:24 PM writes...

"It's also worth wondering if these serotonergic activities help or hurt the drug in oncology indications."

This jogged loose from my mental rolodex (+ PubMed):

Science. 1989 Jun 2;244(4908):1057-62.
Ectopic expression of the serotonin 1c receptor and the triggering of malignant transformation.

Julius D, Livelli TJ, Jessell TM, Axel R.
Department of Biochemistry and Molecular Biophysics, College of Physicians and Surgeons, Columbia University, New York, NY 10032.

Neurotransmitter receptors are usually restricted to neuronal cells, but the signaling pathways activated by these receptors are widely distributed in both neural and non-neural cells. The functional consequences of activating a brain-specific neurotransmitter receptor, the serotonin 5HT1c receptor, in the unnatural environment of a fibroblast were examined. Introduction of functional 5HT1c receptors into NIH 3T3 cells results, at high frequency, in the generation of transformed foci. Moreover, the generation and maintenance of transformed foci requires continued activation of the serotonin receptor. In addition, the injection of cells derived from transformed foci into nude mice results in the generation of tumors. The serotonin 5HT1c receptor therefore functions as a protooncogene when expressed in NIH 3T3 fibroblasts.

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9. Trottelreiner on June 25, 2012 6:59 PM writes...

Err, please forgive me, but wasn't it 5-HT2b AGONISM, as in fenfluramine and some ergot derivatives, that was involved with cardiotoxicity, e.g. inappropiate proliferation of heart valve tissue? If such, 5-HT2b antagonism being somewhat antiproliferative might help with an antitumour agent.

Though of course, it would interact with normal tissue homeostatis. No idea about central effects.

As for 5-HT2c antagonism, 5-HT2c agonists like chlorophenylpiperazine are panicogens in some, but then, so is caffeine. They are also anorexiogenic, vide again, as above, fenfluramine, besides 5-HT release. 5-HT2c antagonism is quite frequent with atypical antipsychotics, too, where it might account for some anxiolysis and the weight gain, and thus nasty things like diabetes etc. But then again, a little more weigth might be benificial with the usual effects of chemotherapy.

Maybe this accounts for some of the side-effects, e.g. hypertension, but then again, there is ketanserin, a 5-HT2a antagonist that is used as an antihypertensive, and most agents acting on the 5-HT2 receptors are not that selective, so I guesss it shares some pharmacology with this kinase inhibitor; though with ketanserin, AFAIR the 5-HTa and 5-HT2c are strongest affected, while here it is 5-HT2b, and then, adrenergic receptors play a dominant role in the effects of ketanserin.

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10. Biotechtranslated on June 25, 2012 7:30 PM writes...


You are right, the cardiotoxicity issues around 5-HT2b are with the agonists, not antagonists.


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11. Philip on June 25, 2012 7:45 PM writes...

@12 Trottelreiner and @3 Biotechtranslated , I thought Lorcaserin was an almost pure 5-HT2c agonist that maybe used for weight loss because it induces a feeling of satiety. Combined with phentermine it is billed by some as a safe FenPhen, because it is not an 5-HT2b agonist like fluramine.

As of this time Lorcaserin is not an FDA approved drug.

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12. DCRogers on June 25, 2012 8:03 PM writes...

A simple Naive Bayes model built from MDDR scores this compound quite high for 5-HT2c, with high scores also for 5-HT2b and 5-HT1d.

My point being, automated data-mining methods for side-effects would likely have signaled these areas for testing.

That said, I agree with Derek that we indeed still have a lot to learn.

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13. Sisyphus on June 25, 2012 10:24 PM writes...

I agree with (7)Twelve. Easy way to get a publication, but this should have been known already. that I think of it, I can republish all of those dirty compounds, multiple times.

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14. MolecularGeek on June 26, 2012 8:03 AM writes...

Twelve and Sisyphus: I don't think that anyone doubts that there are high affinity results for sorafenib at 5HT2mumble receptors in the assay databases of the Wonder Drug Company. But if they choose not to disclose this information, this is still a novel discovery. If registration of an NDA required a full panel of common target binding assays, Bioprint wouldn't be nearly so useful/expensive/in demand. As long as the work came out of their own (hopefully hypothesis-driven) research, and the nanomolar affinity hasn't been publicly disclosed before, I'll stand with Derek that this is an interesting and novel result. It may not have the same sexiness factor as a first-in-class therapy or a new target, but as long as this sort of data is perceived to have commercial value and hoarded by industry, academics independently discovering/disclosing these data are perfoming a service to the community.


(disclosure: as a modeler, I'm a big fan of the resources Bryan Roth provides at PDSP. Lots of good baseline data for CNS targets, even if they are too sparse for detailed SAR.)

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15. petros on June 26, 2012 8:53 AM writes...

Interesting and as highlighted doubtless already information on file in the WDF's computer databases.

Sorafenib looks dirtier and dirtier given the interactions that Kinaxo had previously identified with proteins in the mTOR cascade.

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16. researchfella on June 26, 2012 10:37 PM writes...

@Twelve re: "Those 5HT receptors are all on the commercially available list...". Well, that's fine but I'm not sure what was available in the broad screens back in the mid-90's when sorafenib was nominated as a clinical candidate. And frankly, does it really matter? The risk/benefit ratio for sorafnib is clearly pretty good. Countless cancer patients are benefiting from this drug, and in terms of sales revenue it is a bonafide blockbuster. It hardly seems appropriate to call the sorafenib discovery scientists "jokers" and their achievement "amateur hour all the way around".

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17. Anonymous on June 27, 2012 4:28 PM writes...

here is an article concerning the model in this article:

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18. tiM May on June 28, 2012 9:15 PM writes...


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