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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: derekb.lowe@gmail.com Twitter: Dereklowe

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June 3, 2013

Chemical Biology Highlights

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Posted by Derek

Here's a worthwhile paper from Donna Huryn, Lynn Resnick, and Peter Wipf on the academic contributions to chemical biology in recent years. They're not only listing what's been done, they're looking at the pluses and minuses of going after probe/tool compounds in this setting:

The academic setting provides a unique environment distinct from traditional pharmaceutical or biotechnology companies, which may foster success and long-term value of certain types of probe discovery projects while proving unsuitable for others. The ability to launch exploratory high risk and high novelty projects from both chemistry and biology perspectives, for example, testing the potential of unconventional chemotypes such as organometallic complexes, is one such distinction. Other advantages include the ability to work without overly constrained deadlines and to pursue projects that are not expected to reap commercial rewards, criteria and constraints that are common in “big pharma.” Furthermore, projects to identify tool molecules in an academic setting often benefit from access to unique and highly specialized biological assays and/or synthetic chemistry expertise that emerge from innovative basic science discoveries. Indeed, recent data show that the portfolios of academic drug discovery centers contain a larger percentage of long-term, high-risk projects compared to the pharmaceutical industry. In addition, many centers focus more strongly on orphan diseases and disorders of third world countries than commercial research organizations. In contrast, programs that might be less successful in an academic setting are those that require significant resources (personnel, equipment, and funding) that may be difficult to sustain in a university setting. Projects whose goals are not consistent with the educational mission of the university and cannot provide appropriate training and/or content for publications or theses would also be better suited for a commercial enterprise.

Well put. You have to choose carefully (just as commercial enterprises have to), but there are real opportunities to do something that's useful, interesting, and probably wouldn't be done anywhere else. The examples in this paper are sensors of reactive oxygen species, a GPR30 ligand, HSP70 ligands, an unusual CB2 agonist (among other things), and a probe of beta-amyloid.

I agree completely with the authors' conclusion - there's plenty of work for everyone:

By continuing to take advantage of the special expertise resident in university settings and the ability to pursue novel projects that may have limited commercial value, probes from academic researchers can continue to provide valuable tools for biomedical researchers. Furthermore, the current environment in the commercial drug discovery arena may lead to even greater reliance on academia for identifying suitable probe and lead structures and other tools to interrogate biological phenomena. We believe that the collaboration of chemists who apply sound chemical concepts and innovative structural design, biologists who are fully committed to mechanism of action studies, institutions that understand portfolio building and risk sharing in IP licensing, and funding mechanisms dedicated to provide resources leading to the launch of phase 1 studies will provide many future successful case studies toward novel therapeutic breakthroughs.

But it's worth remembered that bad chemical biology is as bad as anything in the business. You have the chance to be useless in two fields at once, and bore people across a whole swath of science. Getting a good probe compound is not like sitting around waiting for the dessert cart to come - there's a lot of chemistry to be done, and some biology that's going to be tricky almost by definition. The examples in this paper should spur people on to do the good stuff.

Comments (4) + TrackBacks (0) | Category: Chemical Biology


COMMENTS

1. will on June 3, 2013 3:50 PM writes...

"Furthermore, projects to identify tool molecules in an academic setting often benefit from access to ....synthetic chemistry expertise that emerge from innovative basic science discoveries."

Is that really true? Does the Wipf group (or any academic research group) really have more synthetic expertise than a med chem group at large pharma co? granted, the PI has more experience making large complex molecules, but the PI is not running the reactions. instead, you have grad students and post docs with only a few years experience...

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2. Ned Ludd on June 3, 2013 10:49 PM writes...

Dereck, any comments on the recent re-litigation of Avandia and Dr. Nissen's continued campaign to appoint himself the head of the FDA?

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3. Lyle Langley on June 4, 2013 7:16 AM writes...

@will, #1,

I don't think it's an argument of "who is a better synthetic chemist", but more of a "who is willing to do virtually any chemistry to make a compound". Obviously, the industrial medicinal chemists all trained with people like Dr. Wipf, but they are in a setting now where time is more valuable than anything else and as such, they wouldn't go after some of the molecules that are highlighted in this manuscript (molecules, by the way, that are not the best examples of academic contributions). So, yes, medicinal chemists "could" be as synthetically capable as the Wipf group, but due to practical considerations don't have to be. Although, it could be argued that many industrial medicinal chemists simply make the easy compounds using cross-coupling techniques rather than going after the more interesting (and challenging) non-planar molecules. Plus, even though these medicinal chemists have more experience, when is the last time they performed a multi-step synthesis such as a total synthesis? I'm not calling all chemists out, because I am one of these experienced medicinal chemists, but the complex synthetic experience is now 12-13 years behind me. But let me at that next amide coupling, or SnAr reaction....

(Full disclosure, I trained with Dr. Wipf).

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4. NoDrugsNoJobs on June 5, 2013 9:34 AM writes...

Agree with Lyle, I think its that the industrial chemists have lots of pressure for number throughput versus academic setting where the complexity and structural uniqueness of a compound can make it a good target whereas in industry it probably would be not considered.

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