These are my notes from lecture 15 of Harvard’s Chemistry 101: Chemical Biology Towards Precision Medicine course, taught by Dr. Stuart Schreiber on October 27, 2015.
Funding sources for chemical biology research
There are currently ~5 major funding sources for chemical biology research in the United States:
- Investigator-initiated, hypothesis-driven grants from NIH or NSF, such as the R01.
- NIH “U” and “P” contract mechanisms, where NIH issues a request for proposals (RFP) describing the work to be done. It’s usually a consortium of many academic centers and involves ~5 years of work. Past examples have included the National Cancer Institute’s Initiative for Chemical Genomics, or the Molecular Library Initiative’s Probe Development Center Network (MLPCN). Under these mechanisms, academic labs almost become contractors to the government.
- Philanthropic and not-for-profit organizations. Examples include Medicines for Malaria Venture, the Bill and Melinda Gates Foundation, and the Helmsley Charitable Trust Fund.
- Federal and state programs aimed at overcoming the “valley of death” phenomenon. For instance, the National Center for Advancement of Translational Science (see also Cures Acceleration Network (CAN) legislation), and state programs in certain states including California and Texas.
- Public-private ventures, usually between pharmaceutical companies and academic centers. For one lab’s story of how they’ve negotiated the differences in interests between these two parties, see [Michaudel 2015].
When Dr. Schreiber began his career, #1 was basically the only available mechanism. #2 - #5 are new in the last couple of decades.
Success stories in probe discovery through diversity-oriented synthesis
Here are some examples discussed in class:
- Highly selective kinase inhibitors. Most kinase inhibitors are only somewhat selective, inhibiting tens of the ~400 known protein kinases. ~99% of these small molecles bind to cofactor binding sites, which are pretty well-conserved across kinases, hence it’s difficult to achieve selectivity. One exception to this is rapamycin, which binds a different surface of the mTOR protein where it recruits FKBP12, creating a steric blockade to substrate entry. We also discussed other exceptions, discovered in DOS libraries, that achieve exquisite selectivity by binding allosterically and competing with substrates.
- Novel mechanism of action antimalarials. We discussed spiroindolones [Rottmann 2010]. For target identification, they selected for resistant strains and then sequenced them. They identified the target as ATPase 4, which P. falciparum uses to export sodium against the ionic gradient of the host cell. The spiroindolones were discovered through screening only 10,000 DOS compounds and 2,000 natural products. In contrast, around the same time, GlaxoSmithKline screened nearly 2 million compounds of a conventional library and had more limited success [Gamo 2010].
- ErbB4 pathway. The ErbB4 signaling pathway shows some evidence of association with both cancer and schizophrenia. Steve Haggarty developed an assay for this pathway’s activity, see lecture 6, [Kuai 2011]. One good probe for that pathway came out of a build/couple/pair diversity pathway [Gray 2008].
- Transcription factor / DNA interactions. Jared Shaw and co-workers developed a fluorescence polarization assay to look for compounds that would disrupt the interaction between the transcription factor HOXA13 and DNA. They identified a probe that was produced through a build/couple/pair strategy [Ng 2007]. It is worth remembering that although there are no drugs that target transcription factors, there are several probes.
- Sonic hedgehog inhibitors. The ‘smoothened’ pathway signals through a GPCR, which has led to that pathway being considered druggable. There are now multiple agonists known, including SAG and purmorphamine, and Genentech owns one of them. Upstream of or parallel to ‘smoothened’ lie the hedgehog pathways: Sonic hedgehog, Indian hedgehog, and desert hedgehog, which signal through something called ‘Patched’. These are considered ‘undruggable’. But diversity oriented synthesis yielded a hedgehog inhibitor called robotnikinin [Stanton 2009].