Chickens…Roosting…Palbociclib (slightly geekish)

Palbociclib. Who names these things??

See poll below on job posting at the NYT.

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Pfizer recently announced a new drug for the treatment of cancer.  When I saw the article on the NYTimes, I immediately recognized it as a kinase inhibitor.  That’s a class of proteins I worked on in my former life.  There are a bajillion of these little suckers in the cells and they fall into different categories.  They’re important to cancer research because they are some of the culprits that go awry and cause uncontrolled cell growth.  I have never worked on the particular kinase that Pfizer targeted with Palbociclib but just looking at the structure of the drug told me a little bit about how this new drug worked.

First, all kinases have a “hinge” between the two lobes of the protein.  It’s where ATP binds in the native state so that’s where most drug discovery efforts go first to design a drug to block the interaction of ATP with the hinge.  Some drugs bind directly to the hinge in a manner similar to ATP.  I haven’t seen the binding mode of this particular drug so I don’t know that it is a hinge binder.  There is a significant limitation to developing hinge binders and ATP competitive inhibitors: if every kinase has a hinge, isn’t it just as likely that your drug will affect more than one kinase?  Yes!  This is called a selectivity problem and it’s a common obstacle to overcome in kinase projects.  The likelihood that your drug will hit something else that it shouldn’t is higher with ATP competitive inhibitors.  Drug design in this area requires precision.

Second, the article says that the effect of the drug is nothing short of amazing – at first.  Unfortunately, survival time is not significantly increased for the patients.  Now, why is that?  There could be a number of reasons.  The cell is really complex and has a lot of moving parts and cancer cells have a tendency to pump drugs out of themselves.  If you know of anyone who’s been on multiple rounds of chemo, it’s probably because the cells have been able to become resistant to the first line of defensive drugs.  But there are other possibilities  besides the cell pumping the drug out.  The lack of selectivity could be affecting a closely related kinase directly upstream of the kinase that is targeted.  Or it could be that the inhibition of the kinase you are targeting causes the upstream kinase to overcompensate causing up regulation (over expression) of your targeted kinase, which kind of defeats the purpose.  So, you may get some real quality time with your family for most of the length of the time of your treatment but then the whole thing goes FUBAR very, very quickly.

Sound complicated?  That’s because it is.  And that, oh best beloveds, is why cancer is so damned hard to cure.  There are multiple moving parts in the cell and they play with each other in complex ways.  It makes high frequency trading flash bombs on the stock market look simple by comparison.

There are some other interesting features of this drug structure.  I see that it has a protonated nitrogen in the piperazine, which is likely making a H-bonding interaction with a carbonyl or carboxylic acid at the lip of the binding site under the glycine rich loop.  I find the cyclopentane ring intriguing.  I’d love to see the structural biology related to this series to see if I could tweak the residues in the glycine rich loop close to the hinge or push the gatekeeper residue to open up the back pocket…

Oh, wait, that’s right.  The industry laid most of us off, “because we are too menny“.  And besides, I don’t have a PhD and, therefore, I am unemployable in the area that I have decades of experience.  Oh well.

On the other hand, it’s a bit weird to see that in the 3 years since I worked on drugs very similar to this one, there hasn’t been a lot of progress.  It’s very likely that Pfizer has already moved on to a new series or maybe it just gave up on this kinase and this is the best you’re going to get so they decided to stop beating on it and develop this lead.  Hard to say.  One thing is for sure.  Cancer patients make very good customers.  They’re desperate, willing to sell their first born for a potential cure and they aren’t likely to sue you for side effects. So, many companies have decided to focus on cancer and orphan drugs, another potentially lucrative area, while abandoning less profitable areas like antibiotics and CNS drugs that come with the tricky blood-brain barrier problem.

Billionaires are starting to get into the act now.  The high tech billionaires seem to think they can apply the lessons learned from Silicon Valley to the biotech industry.  Yup, just make the whole process of drug discovery more efficient so it can go faster.  Or something.  Just ignore the complexity of the cell.  If we incentivize the geniuses, they will be stop dawdling and get the drugs to market.

Over at In the Pipeline, Derek Lowe’s most excellent blog on the ups and downs (mostly downs) 0f working in pharma R&D, I found a link to a recent article in Forbes by analyst Matthew Herper called “Three Misplaced Assumptions That Could End the Biotech Boom“.  The biotech sector has suffered a shock lately.  It seems like investors are having an “Oh $#*^!” moment as they are starting to realize that outsourcing everything for shareholder value, hiring all of China and India with all of the rapid turnover and falsified data that goes with it, and pushing the small pool of brilliant geniuses in Cambridge and San Francisco to “go faster” isn’t working very well.  The failure rate of drugs advanced for approval is still something like 90%.

Herper cites three reasons why biotech is suffering, the most important one is that in spite of all of the shareholder, billionaire and MBA interventions, the decline in R&D productivity hasn’t slowed.  I’m going to guess that this is directly related to the new revolution we are facing in biology.  The more we know, the more complex the system has become.  It is going to take a lot of time and many minds to sort through all the data to figure out how best, and safely, to put it to use.  Short term profit making is incompatible with this kind of R&D research.  Investors are going to have to sink a lot of money into the system and wait a relatively long period of time for results.  There are no shortcuts, as many of them are discovering.

Duh.  We could have told them that before we were laid off en masse.  What a shame.  All those millions of hours of experience in hundreds of thousands of researchers have been sitting on the shelf for several years while the billionaires attempt to reinvent the wheel and the MBAs apply the latest schemes to split up the R&D units and have them all compete with each other in order to maximize shareholder value.

{{sigh}}

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In other news, the kitchen is almost done.  I’m painting, Ok??  I have to paint over high gloss oil based paint (curse the former owners).

But while I was procrastinating, I found a very interesting link to a job opening at the New York Times in my Twitter stream. It’s for a “Writer, Opinion App Job”.  Except for the preferred three years of journalism experience, I could do this job.  Should I apply?  Take the quiz.

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And now for something Hot and Naughty from Titli Nihaan: