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"You might have to speak louder," advised Peter Wipf, chemistry
professor at the University of Pittsburgh. "There's a concert
going on outside my office. Someone named Bon Jovi."
In fact, rock star Jon Bon Jovi was at Pittsburgh this April headlining
a rally for presidential hopeful Sen. John F. Kerry (D-Mass.)
as part of the candidate's campus tour. The presence of this '80s
icon at a major 2004 event was indicative of a trend celebrities
have relied on for decades: Evolving your image can expand your
popularity well past the 15-minute mark.
In the pharmaceutical industry, combinatorial chemistry was
the major pop star of the 1990s. This process of rapidly making
millions of compounds through parallel synthesis and screening
them against target proteins for drug candidates seemed to be
the wave of the future.
During the initial fervor, drugmakers encouraged chemists to
explore high-throughput synthesis in hopes of revolutionizing
productivity. Ten years later, with the promise of brimming drug
pipelines unfulfilled, combinatorial chemistry's 15 minutes of
fame appeared to be at an end.
"The initial idea was, 'We'll make millions of compounds, and
one will be your drug.' That's just unrealistic," says Samuel
Gerritz, group leader for lead synthesis at Bristol-Myers
Squibb, in Wallingford, Conn. "In hindsight, I'm surprised
how many of us bought into it."
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Czarnik
COURTESY OF ANTHONY CZARNIK |
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In the early days, combinatorial chemistry created lots of mixtures,
and the quality of the libraries, even for discrete compounds,
was insufficient, says Rongshi Li, head of high-throughput chemistry
at ChemBridge Research
Laboratories (CRL) in San Diego. Impurities in these early
libraries led to many false-positive hits during screening, which
generated negative attitudes toward their use in drug discovery.
Nevertheless, the techniques of combinatorial chemistry have
evolved to be incorporated into the standard job of drugmaking,
and they continue to change as synthetic organic and other chemists
in the field make improvements and adaptations. Like Bon Jovi,
the updated version of combinatorial chemistry still has its fans
and is still headlining key research in the pharmaceutical industry.
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Gerritz
COURTESY OF SAMUEL GERRITZ |
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"Right now is a relatively good time for synthetic organic chemists
to be looking for a job," says Anthony
W. Czarnik, visiting chemistry professor at the University
of Nevada, Reno, and editor of the Journal
of Combinatorial Chemistry. As chemists move up the industry
ladder, "there's a constant need for new blood doing the actual
chemistry in pharmaceuticals," he says.
STATISTICALLY,
at least, the pharmaceutical industry has been holding
its own in terms of hiring. A decrease of 67,000 jobs for the
chemical industry as a whole between 2000 and 2003 was tempered
by an increase of 27,000 new hires in pharmaceuticals between
2001 and 2003 (C&EN,
Jan. 19, page 11).
What's more, Czarnik says, almost every pharmaceutical company
uses combinatorial chemistry or parallel synthesis in some fashion.
"These tools are really being integrated into the everyday work
of medicinal chemists," he says.
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Maag
COURTESY OF ROCHE |
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Gerritz believes combinatorial chemistry is a powerful tool in
drug discovery that shouldn't be abandoned because it didn't live
up to the early hype. "Today employers expect that you are familiar
with the concepts of combinatorial chemistry," he says. "It's becoming
part of the natural skill set for synthetic chemists in industry."
Currently, the majority of openings in pharmaceuticals are
for people with good basic skills and innovative ideas, says Wipf,
who is also director of Pittsburgh's
Combinatorial Chemistry Center. The recent string of mergers
at big pharmaceutical companies generated hiring freezes and employee
redistribution that impacted the job market for new graduates,
he says. Companies are still hiring, but they are able to be more
particular, conducting more thorough background checks and emphasizing
softer skills.
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Wipf
COURTESY OF PETER WIPF |
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According to Li, "A good synthetic chemist can always find a job
regardless of the market." Good candidates, he says, display creativity,
a sound knowledge of modern synthesis methods, problem-solving
skills, and the ability to work in multidisciplinary teams.
"Combinatorial chemistry is a skill in addition to the basic
synthetic chemistry skills," Li says. "Chemists can use it to
synthesize desired compound libraries, move from hit to lead,
and conduct hit follow-up in the most efficient manner."
Hans Maag, vice president of chemistry at Roche, Palo Alto,
Calif., believes that the heyday for combinatorial chemistry in
big pharmaceutical companies has passed, but that parallel synthesis
is and will continue to be a useful tool for medicinal chemistry.
"If a candidate has experience in parallel or solid-phase synthesis,
that adds to their skill set, but we don't go out looking for
someone who has done massive numbers of reactions," Maag says.
Instead, he primarily looks for excellence in synthetic organic
chemistry, plus qualities such as independent thinking and an
engagement with science.
According to Czarnik, the actual work of synthesizing large
libraries of compounds is most often outsourced to smaller start-up
firms. These companies make and characterize libraries of diverse
compounds that are then transferred to larger companies for screening.
CRL is one of these small contracting firms. Its parent company,
ChemBridge Corp., employs
about 350 people worldwide and contracts chemistry services with
large drug companies such as Pfizer
and Merck. Using the existing
ChemBridge portfolio, CRL expands beyond pharmaceuticals to contract
with biotech companies and to develop its own unique libraries
for drug discovery.
At Roche, Maag says, compound
libraries are outsourced in this fashion, but internal researchers
also apply parallel synthesis to lead optimization. The work done
by employees involves much smaller libraries of compounds generated
in traditional labs. "The size of the sets we create has gone
down to 20 to 50 compounds," he says. "Even the libraries we outsource
have become smaller."
Li also thinks smaller, more diverse libraries are a better
path to increasing hits. In the early days of combinatorial chemistry,
he says, companies were "playing the numbers game," trying to
see who could create the largest library, usually from a single
core compound. But having thousands of compounds based on the
same scaffold doesn't actually improve the hit rate, he says.
"Well-designed small-molecule libraries using drug-relevant building
blocks and biologically privileged scaffolds can provide better
coverage of biological targets and druglike chemical spaces, enhancing
the chances of lead discovery," Li says.
"The term 'high-throughput synthesis' is undergoing constant
redefinition," Wipf says. When it was first introduced, high-throughput
meant hundreds of thousands of similar compounds, he says. Since
then, it has been scaled down to mean hundreds to thousands of
distinct compounds. Wipf also notes that diversity-oriented synthesis--using
combinatorial methods to create many different compound skeletons
that have high potential for appendages--could once again transform
what high-throughput means for drugmakers.
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LEARNING BY DOING In the pharmaceutical industry,
synthetic organic chemists are expected to learn drug discovery
skills on the job that eventually transform them into medicinal
chemists.
COURTESY OF ROCHE |
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THE CONSTANT EVOLUTION
of what can still count as a fledgling field means that
working in combinatorial chemistry can be as much about personality
as about technical skill. According to Gerritz, being adaptable
and open to new challenges are key attributes for the combinatorial
chemist. While earning a Ph.D. from Massachusetts
Institute of Technology, Gerritz worked under the late Satoru
Masamune, a man he describes as "fearless" about diving into different
areas of chemistry.
"I was working on a traditional total synthesis project, but
[Masamune] taught me to not be afraid to leave my comfort zone,"
he says. After graduating in 1993 during the height of the combinatorial
craze, Gerritz took a job with Glaxo,
where he plunged into the very nontraditional field of high-throughput
synthesis. "In 1995, we had to invent or adapt everything," he
says, referring to the dearth of specialized lab equipment in
the early days of the field.
Reaction protocols for one-at-a-time compound synthesis also
had to be reinvented to apply to parallel synthesis churning out
thousands of compounds.
"This field attracts the type of person who is never fully
satisfied with the way things are," Gerritz says. "You always
look for more efficient ways of handling so many compounds--you
want to improve the process."
Now, as a group leader at Bristol-Myers
Squibb, Gerritz is applying his hands-on experience to planning
synthesis efforts and coordinating library creation with the needs
of ongoing discovery projects. Although his synthesis projects
these days have been scaled back to a mere 50 to 100 compounds
produced in a week, Gerritz is appreciative of the speed and efficiency
that combinatorial methods have contributed to drug discovery.
"I would be surprised if the majority of compounds entering
clinical trials in 2004 have not been impacted in one way or another
by combinatorial chemistry," he says.
Li also got his start in combinatorial chemistry in 1993, when
he was a postdoctoral fellow at the University
of California, San Francisco. His work building combinatorial
libraries in a structure-based protease-inhibitor-design program
led to a job in the chemistry division of start-up firm Irori,
which later became ChemRx, a part of Discovery
Partners International. During this time, Li directed sorting
technology, developed combinatorial protocols, and synthesized
vast discrete-compound libraries for pharmaceutical and agricultural
companies.
Since joining CRL in 2001, Li says he has been actively involved
in recruiting chemists for the firm, although recruitment has
lessened over time. In general, Li says experience in high-throughput
methods is a plus for candidates, and whether that experience
comes from academe or industry is immaterial. "No matter where
a candidate has had training, they will still need some kind of
additional training" when starting work at a new company, he says.
Wipf agrees. "From the academic point of view, we try to make
sure our graduates have the skill sets to succeed in industry,
but we don't want to cater exclusively to industry," he says.
Instead, he explains, universities must give students a broad
foundation that will allow them to adapt to new technologies over
a 30- or 40-year career. "The main job of academia is to turn
students into problem solvers," he says.
Within the pharmaceutical industry, synthetic organic chemists
can be hired for many different positions with vastly different
requirements, so a traditional background remains paramount. Still,
Wipf says, the academic environment must provide students with
an infrastructure that matches the modern tools of industry. "The
equipment they learn with must be representative of the 21st century,"
he says. "Our facilities and tools must be updated continuously."
For example, today one of the basics all his students learn is
the ability to access and critically evaluate the vast array of
data made available by databases and the Internet.
For today's chemists interested in working at small combinatorial
contract firms like CRL, a background in physical organic chemistry
might be a better fit than traditional synthesis, Czarnik says.
"It's a little like doing production: You optimize rates, optimize
yield, test purity--skills that are useful for making libraries
but less essential for drug discovery."
According to Czarnik, working for small combinatorial start-ups
offers the benefit of owning stock early in your career, but it
can challenge chemists not used to rigorous deadline pressure.
"At large firms, chemists are expected to work long hours per
week and do their best, but in the end whatever you produce is
what you produce," he says.
At smaller firms, contract deadlines must meet clients' expectations,
although the general rule is that deadlines can be broken for
the sake of quality. "High-throughput synthesis shouldn't become
a worker-bee environment," Wipf says. Instead, it is a tool that
allows students to do auxiliary work more quickly so that they
can focus on the design of creative chemistry. "Ultimately, the
most important thing is the compound we synthesize, not the devices
we use," he says.
No matter what type of employer seems most appealing, Czarnik
says, "it's much more important to get that first job than to
wait for your first job at a specific company." Simply doing the
job and talking with coworkers helps recent graduates learn what
it is like to work for different employers. If the first job doesn't
satisfy, good training and industry experience make mobility much
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