Today is my first day with a small privately held biotech company that is developing self-assembling polymers for targeted drug delivery. The group and the projects are awesome – and as much as I am excited about the research and the company, for obvious reasons I shouldn’t be writing about it. So there will be nothing new to add here. This is it – thank you for visiting!
June 23, 2011
April 22, 2009
I would like to direct the readers here to the excellent project-and-career story from Bruce Maryanoff in the most recent J. Med. Chem ASAP. It is very illuminating on how the drug discovery and development works, and it describes in some detail what a bright chemist can hope to achieve in this profession -with the necessary motivation and a decent employer (and tremendous amounts of luck).
It is also an illuminating story on how the process does not work. For example, the currently most popular, target-driven rational-design-based approach can be pretty futile in CNS drug projects . The author also suggests that the management mantra about focusing on the discovery of the next “blockbuster drug” actually bankrupts the industry – financially and scientifically; his drug Topiramate (which has been making 2 billions a year for the company) would have not been discovered or developed under the management methods currently prevalent in the industry. Few things stand out: 1) It seems that having a blind luck and testing the compounds in a realistic animal model is more important than having a correct mechanistic understanding how the drug candidate actually works. 2) Few independent-minded individuals in their pharmacology and chemistry have made a good use of their lucky break. They stubbornly kept the research program going – even as their managers were lukewarm and would not support the compound development for a long time. It also goes to the credit of the management that allowed their researchers to pursue this as their hobby. The story shows that the progress in pharma research does not really happen by imposing some management-theory-derived reporting structure on the research department, by drafting the flowcharts and aligning the teams. For medchem research to succeed, the projects should be allowed to self-organize around the bright individuals rather than being planed out from top down, with red tape and micromanagement.
In this context it is entertaining to read rather disingenuous remarks made by the Merck chief strategy officer Merv Turner at the pharma management conference. He explained that they are currently sacking lots of people in research because “Seventy-five cents of every dollar we spend on R&D goes to fund failure” and “the future results must come at a lower cost”.
The actual drug discovery cost makes only few percent of the final drug development cost. By far the most expensive part is the clinical trials and namelly the late-stage clinical trials. What the Merck management poseurs do not tell in public is that it was the Merck top management decisions that cemented their company’s commitment to these “the next blockbuster” projects – which eventually led to a string of stunningly expensive late-stage failures. When the top executives receive massive stock option bonuses, they become mercenaries of the stock prices. Their wishful thinking baloney percolates from top down through the management layers, etc.
There are many parallels between the state of pharma industry and the recent financial sector collapse, and it is always the executives who run their companies to the ground that are rewarding themselves most obscenely. Remember this whenever the pharma companies claim that the freedom to price their drugs is essential for the innovation.
August 11, 2008
Derek Lowe of the Pipeline wrote a very insightful column in the last Chemistry World issue, about the narrow repertoire of synthetic methods used in medchem projects. His take is that the need for cranking out compounds for testing (=as many as possible) drives the chemists towards fool-proof reactions with a good functional group compatibility and building block commercial availability. The narrow choice often leads to insoluble series with poor oral availability and PK problems and insufficient structural diversity. More serious still is the turn-off effect on the chemists:
…For one thing, skills do need to be kept sharp, and running a variety of different chemistries is the best way to do that. And safety seminars aside, medicinal chemists do not actually have limitless capacities for boredom. Running yet another long line of palladium coupling reactions or amine displacements begins, after a while, to feel like working at a sawmill. The blade takes longer to cut through some of the logs than others, but the boards all come out looking about the same.
I think the problem of poor solubility and ugly design became more serious with the advent of kinase projects; the kinase slit-like binding sites typically extend far enough to accommodate ligands consisting of multiple aryl rings put together like beads on a string. Gleevec, Lapatinib, Dasatinib have this sort of structure – but then again, various ugly molecules are used in cancer treatment; I am unsure if this design will work for other therapeutic areas also. (I have been making kinase compounds for a good part of this decade and I still like the smaller + more compact molecules better).
I met a number of chemists in the industry that already gave up on reading journals – their argument was that there were too many journals and too many articles and most of it was not very useful to them and whenever they needed to find a reaction the Scifinder and Beilstein-Crossfire search engines did adequate job. (Which is true). But I noticed that one typically loses his chemistry interest about the same time when he stops reading the literature; I don’t know what is the cause and the effect here.
More than 90% of synthetic chemistry is routine stuff – and frequently frustrating one, too. There are easier and healthier professions to chose from. I believe that most people got into synthetic chemistry because they experienced a sense of wonder, and they just kept coming back for more. Mixing up obscure, dangerous chemicals to obtain shiny crystals at the end is a pretty awesome and esoteric way to make living. Designing your own experiments and figuring out their problems, inventing tricks to make the chemistry work, trying your nutty ideas (to see if they translate into good compounds) is enormously gratifying experience. If the curiosity is quenched and the excitement is taken away all what’s left is shaking the sep funnels, putting flasks on the rotovap and analyzing fractions as they come off the column…
There are various non-chemistry reasons why someone stops enjoying his particular project (personal-life problems, the lack of support, evil boss, problems with biology, the bureaucracy and politics, etc.) and the way to go about those difficulties is obvious. Instead I have few chemistry-related suggestions what to try, when the boredom and frustration takes over and the project becomes unsufferable:
1. Scaling-up. When chemistry does not work try some easy reliable procedure. Pushing through bulk material such as a commonly-used building block or an essential reagent that you made before helps to boost your self-confidence in times when your other chemistry failed you. Making a flask full of bright-yellow crystals is deeply satisfying and when you filter them, dry them and put them in a bottle with a pretty label, when the NMR is clean, at least you don’t feel like a hack anymore. Besides if the material is useful to your group passing it selflessly around will make you popular.
2. Fluorine chemistry: Too many chemists opt to buy the fluorine-containing pieces without worrying how these molecules are made. There is a growing number of organofluorine building blocks available, companies like Apollo have a fat catalog full of them – but many important pieces are not available and easy chemistry to prepare them exists. Medicinal chemists shouldn’t be exhorted to work with F2 or anhydrous HF – but reagents like Deoxyfluor, Selectfluor, (PhSO2)2NF, NEt3.3HF are commercial, affordable, and are not too difficult to use (if the necessary precautions are taken). Many people are simply unaware that metabolically-stable difluoromethoxy group is readily introduced on a phenol OH by alkylating it with difluorocarbene (which is produced from chlorodifloroacetic acid) or that ArCF2CO2Et is easily made from Aryl iodides, BrCF2CO2Et and activated copper metal in DMSO under mild conditions, that CF3 group can be introduced on aryl iodides with equal ease with catalytic CuI and sodium trifuloroacetate, that difluorocarbene in presence of PPh3 produces a Wittig reagent (that converts aldehydes to useful 1,1-difluoroalkenes), that trifluoromethyl anion generated from TMSCF3 adds to imines and aldehydes with ease etc. There is a whole continent of a strange organofluorine chemistry and a medicinal chemist would do well to make himself familiar with these methods because apart from the nastiness of some HF-generating reagents these reactions tend to be well-behaved and predictable.
3. Metallation: Thanks to Schlosser and others there is a body of literature on position-selective lithiations of heterocycles, like pyridines and pyridimines, and there is also older literature on use of ortho-directing groups in benzene metellations. Very often these reactions are done with common reagents like BuLi, LDA, LiTMP, at simple conditions like THF -78C. The functional group tolerability is not as great but this aryl CH-lithiation can be a powerful way of accessing simple building blocks with a special substitution pattern – a great help when changing the centerpiece ring in the series and run into the availability problem.
Mg and Zn chemistry: Knochel is developing beautiful systems, for halogen-metal exchange, and many of his transmetallation reactions using secBu-Grignard and zinc reagents has been promptly adopted by process groups but medicinal chemists are lagging behind. One can easily generate Grignards with ester ot even nitro group in the molecule, by transmetallation, and zinc reagents can provide much cleaner Negishi coupling than their Suzuki boronic acid counterparts.
Schwarz reagent, BBN-H borane: hydrometallation and hydroboration is a great way to access commercially-unavailable building blocks for Pd(0) catalysed cross-coupling reactions. BBN boranes do Suzuki-like sp3-carbon coupling with aryl, vinyl halides.
4. Cyclopropanation: Cyclopropyl substituents are of a great interest to a medicinal chemist on their own but they are great also for ring-opening reactions (they behave as a 3-carbon analog of C=C bond). In my opinion the enormously easy-to-use zinc promoted reactions (CH2I2 with ZnEt2) and titanium-promoted cyclopropanation reactions (Cp2TiCl2 with Grignard) are neglected in medchem projects.
5. Asymmetric methods: There are so many of good ones and yet any medicinal chemist will always look first into buying the chirality – perhaps this has to do with the inconvenience of setting up a chiral column for analysis of the product ee. (One does not have this sort of excuse with chiral auxiliaries). And some of the reactions are exceptionally easy to run, with commercial catalysts and and great functional group tolerance: Noyori Ru-TsDPHEN transfer hydrogenation of ketones, CBS reductions, Sharpless allyllic epoxidation, dihydroxylation and aminohydroxylation, Jacobsen asym epoxidation and epoxide hydrolysis kinetic resolution. There are Rh and Ru-phosphine C=C hydrogenation that go at modest pressures (50psi) and thus can be set on a Parr shaker. There is a whole field of organocatalysis, with simple catalysts like proline, doing great feats on simple aldehyde substrates – several stereocenters at once. I think its mostly the laziness that medicinal chemists do not adopt these reactions more frequently even as most of them get trained to use them in grad school; as soon as they join pharma they learn to weed out the chiral centers from their molecules. Nature is chiral and even as it takes more time and effort to employ the asymmetric methods the methodology investment can be well worth the trouble – with a functional-group tolerant method like Noyori transfer hydrogenation, the development work needs to be done only once – and from then on the chemistry is just as easy to perform as a borohydride reduction.
6. Making your own heterocycles. When you buy a boronic acid piece and slap it onto your molecule you make your final compounds faster – but often it is worth looking into how a particular ring system is made. The chemistry used may be ancient or completely new (Padwa is my hero), one can make everything from TOSMIC, etc. You would be amazed how many 5-membered rings are easily available from aldehyde or carboxylic acid.
7. Screening the ligand/solvent/base etc. Even the robust Pd(0)-catalysed reaction can become finicky for a particular class of substrates. There is the base, Pd-source, ligand, and solvent to choose (apart from the temperature, concentration and time) and if you get one parameter wrong the reaction usually fails or stops at low conversion. Sometimes little time spent on methodology optimization pays off handsomely.
You should care about the chemistry methodology and do things not just to crank out the final compounds to fill up the testing queue. Your boss perhaps lost all his chemistry interest already and maybe he is unnerved about the project progress and pushes people hard – but while you try not to get fired you don’t necessarily want to think like your boss (and end up wretched). If you continue to look at your research project with curiosity and do things also for the sake of your chemistry interest you are likely to be more original because thinking about the methodology will suggest new directions in your medchem project. You may get acused of playing with chemistry and going off-tangent but you will likely remain more content and productive and you will continue to live your life in the lab – which could be a good or bad thing depending on the marriage situation.
August 6, 2008
A colleague stank up the lab at my previous company with a disposable pipette tip from ethanedithiol. He dropped the tip into a trash bin outside his hood; people soon complained so he dumped the bin content into a big garbage container located in our parking lot. It was a searing-hot Arizona summer day with no wind – and the stink got taken in by the A/C system of our neighbour, a robotic engineering company.
The robotic company owned the whole building and needed more space to expand their business. They wanted us out but we had a long-term lease signed with them. For years the robotic guys have been coming up with arguments about how we violated the lease terms. They reported us to EPA repeatedly, for problems like “burying chemical waste in the desert” (they could not provide information where the stuff was burried or the witness that actually saw the incident). We had EPA on us all the time – and whenever the inspectors gave us a surprise visit it was always the robotic company that ended-up fined instead (machine oil spilled on the ground, etc) while we managed a passing grade with each inspection…
This time the robotic guys reported us to the Poison Control Center. Without telling anyone at our company, they complained that we sickened their employees (they instructed their employees to take the day off – and recommended them to report to a hospital for a check-up: they told them otherwise they wouldn’t be eligible for a work-disability compensation in case they would become later ill). The poison control in turn called the military and advised them about a “poison gas release” contaminating the place – and soon the experts from the nearby Air Force base arrived in full gear. Men in bunny suits appeared on the scene, walking slowly about our parking lot and taking samples of everything with the utmost care.
There was a fire station located right next door too and these firemen were not that busy in the spread-out Oro Valley suburbs – they were usually putting out the brush fires on the Catalina foothills and when the desert was not burning they were there at their station hanging about. Their chief was organising drills and sports-like competitions to keep up the morale – occasionaly they were rolling fire hoses or running in their gear up and down our parking lot. So when the space-suit men showed up we were not concerned; and we were rather curious, watching them – we thought the firestation dudes were finally doing something interesting! Then a $50,000 bill came – and with it a lively debate commenced, about who is paying the astronauts.
March 25, 2008
Last week I run a reaction in molten imidazole without a solvent, at 240C in a pressure vessel. This reminds me – in Prague we would heat quantities of beta naphtol with neat hydrazine hydrate in a “Bombenrohr” in the electrical oven at 150C, and we were taking that alarming thing periodically out and giving it a hard shake while hot. (Bombenrohr is a fancy German word for a pipe bomb, a steel tube with screws at ends). The resulting ooziness was then poured and spooned out into vats of boiling water, to extract away the unreacted hydrazine, naphtol and the sideproduct – betanaphtylamine (I know how it smells so I am gonna die) – and the leftover slime was then repeatedly precipitated as HCl salt, to get 1,1′-binaphtyl-2,2′-diamine. We were making 50 g batches of the racemic stuff that way and we were then resolving them with CSA.
The meanest reaction I did was melting binaphtol with 3 equivalents of Ph3PBr2 without solvent, to get binaphtyl dibromide. The procedure called to “dilute the melt with equal volume of dry Celite, cool the mixture to solidification, break the flask and peal off the glass, crush the solidified reaction mixture into half-inch sized chunks and extract them in Soxhlet” – which I managed, except that hammering the mean black 250mL tar-ball into chunks produced lots of corrosive bits flying everywhere while I was choking on the HBr fumes.
There is no moral to this sad story.
February 24, 2008
When I was laid off 2003 by a giant pharma company, we were told that – because we were getting a better severance payment than the absolute minimum required by law – we must sign a gag agreement. The agreement was that we won’t say anything negative about being fired and about the company that fired us. In this gag agreement we also promised that we would not disclose the severance amount and the existence of the gag agreement.
Since our closed site was quite large, they did not fire us all at once but they divided us into “waves” . I was lucky to get out early so I still got what was promised – but the colleagues fired few weeks afer me were screwed. Someone at the headquarters figured out that they were giving away too generous severance so they cut it. Many of my colleagues ended up suing the company: their class-action dragged on for years but eventually the company coughed up the rest of the promised money to settle.
I soon found a job at a medium-sized company in South San Francisco. The place was crazy – they drove us extremely hard there because the company was in trouble and we needed to save it or we would lose our jobs. So we were working like nuts “to have a clinical candidate by the end of the year”and the biggest problem was our management: they were very nervous, they made all kinds of unrealistic promises to appease their superiors but wouldn’t spend money on equipment we needed for the candidate scale-ups. The management was setting us for failure – we were short of people but they would always come up with ridiculous new ideas what else we should do for somebody, ontop of our work. So our medicinal chemistry group ended up doing the scale up, the bulk purifications, the process optimisation, and the formulation work also – while trying to find the best candidate. After 10 months I got tired of this baloney (and our boss) and since I got a job offer I prepared to quit. There was plenty of good chemists there and I talked to some friends discreetly – to see if they would like to go with me – but not discreetly enough and our management found out. And so they decided to fire me preventively. The problem was that they did not have an official reason for firing me – and they would have to pay a severance if they fired me.
The way it happened was rather entertaining: our evil boss came and asked me if the rumor was true – that I would be leaving. I said yes but I would want to stay for another 6 weeks or so, before my new job starts. She said they needed to find a replacement for me and they couldn’t advertise my job because they did not have an open position. So as a favour, please would I write an informal note about the timing so that they could start the hiring process? I wrote the e-mail and the next morning I found myself fired on moment notice. I was called into HR office in administrative building and told I cannot go back because my “written resignation was accelerated” by the HR, and my poor boss could do nothing about it “because it was a standard industry practice”. They would box and mail my stuff.
I asked HR whose idea it was – they told me our boss wanted me out. So I explained the HR that this was a manifest scam: the real reason why they fired me was the argument between me and my group leader. I told the HR the boss was going after me for some time because I criticised her management style and the decisions she made which delayed our project and hurt our company. In these difficult circumstances I did what I could to save our company and was working 14 hours a day including the weekends and I was punished for it – while my boss was trying to fabricate any reasons to fire me in order to cover up her mistakes. Now she did it in a sleazy way and she also manipulated the HR in the process. It was a textbook wrongful dismissal.
The HR immediately called my boss and overruled the firing and I went back to work. The victory lived short: the same evening the boss called an emergency management meeting – all the senior staf, with site director, etc – and she went about the terrible danger that I would steal the company’s intellectual property and lure other employees away. I found myself fired the next Monday.
It took several letters to the company director with “wrongful dismissal” prominently in them – and suddenly I got a check in the mail – over $7000 – and it was much more than they owed me for my unused vacation; it was the money that I would make if I stayed for another 2 months. Incidentally, two months is the minimum severance required by law to be paid to dismissed employees (in California). After the check cleared I got a phone call from the headquarters: their HR boss explained that someone has made a clerical error and they overpaid me by mistake but they did not want me to return their money. You see – they could not call it severance “because I resigned voluntarily and they accelerated it” but they decided to pay my lost income to shut me up.
Some time after I left, my colleagues in South San Francisco were told that there were going to be “some limited job cuts in the future” and they needn’t to worry as the downsizing would affect only few people in some groups but the company was required by law to give a notice of possible job cuts to everybody. What the top management did not tell the employees was that the headquarters already decided to axe the company site no matter what. The top company decision was to quit the pharma business altogether – the only problem was that their research projects were unfinished. To get the best value for their research, the management needed its employees to take the projects to some reasonable stage before they could sell it to other companies. So the harder the people in the labs worked the sooner they would find themselves out of job…
And the notice was a ploy also: the legal minimum severance counts from the moment of the written notification. The employees believed the management promises that their jobs were not in danger (despite the notice) and that they were protected by the company written policies. They were told that those few people who would lose their jobs would get much better severance than the legal minimum. In fact, they did not. One day the employees were invited for all hands meeting in the administrative building and there they were told there that they can’t go back to lab again. Suddenly guards and boxes appeared at the chemistry building and the chemists were given only few minutes to pack their office belonging. They were constantly watched as to not to sabotage anything. Despite the assurances, they all got just the minimum, which turned out to be less than 1 month salary because the notice was already in effect. (The group bosses were employed few weeks or months longer, in the empty building, in order to wrap up the projects and put the documentation together. I suppose they got a better deal.)
So as you can see, the industry has various ways of maximising the shareholders’ value. There is probably someone at your company who will get a bonus for firing you and then screwing you out of your severance.