Many drug discovery researchers think smaller these days, specifically about fragments. “A big trend more specific to small molecule drug discovery is fragment-based drug design (FBDD),” said Molly He, Ph.D., senior scientist at Sunesis Pharmaceuticals (www.sunesis.com). “It has gained increasing popularity among the pharmaceutical and biotech companies because of its ability to access large chemical space using small amounts of compounds—it’s a new paradigm for drug discovery.”
Fragment screening and targeting protein-protein interactions generated considerable buzz at the CHI “Drug Discovery Chemistry 2007” conference. Harren Jhoti, Ph.D., founder and CSO of Astex Therapeutics (www.astex-therapeutics.com), noted that a key reason for the emergence of fragment-based drug discovery is its sheer practicality.
“We only need to have a modest collection of fragments—roughly 2,000; but because they are so small, between 150 and 200 daltons, they can sample so much chemical space. The larger the fragment size in your library, the larger the number of compounds that you are going to need to sample the same amount of chemical space.”
Astex uses a number of biophysical techniques as screening tools including high-throughput x-ray crystallography in its fragment-based discovery approach. “X-ray crystallography is an intelligent methodology and has the advantage of giving the best picture of how the fragment sits in the target, and when paired with NMR allows you to create a structure-based lead,” noted Dr. Jhoti.
Astex’ discovery program utilizes high-throughput x-ray crystallography and NMR to screen fragment libraries. According to Dr. Jhoti, the company has proven that this approach for lead generation has distinct advantages over conventional bioassay-based, high-throughput screening in that low-affinity fragments with novel structures can be identified as starting points for hit-to-lead chemistry.
“These fragment hits can then be rapidly optimized for potency and DMPK properties using iterative cycles of medicinal chemistry and structure-based drug design,” Dr. Jhoti continued. “Our fragment-based drug discovery approach, which we call Pyramid, enables us to handcraft molecules with regard to potency and selectivity, and consequently our molecules tend to be more compact. There is a clear correlation between the size of the molecule and the success of its development. Compounds that are too large tend to be too complex to succeed and suffer high rates of attrition in development.”
Astex has developed lead compounds using this approach for targets such as the cyclin-dependent kinases and aurora kinases, both of which are key proteins involved in cancer. AT7519 and AT9283 were identified using Pyramid and are now being tested in clinical trials as potential anticancer therapies.
“To the best of my knowledge, we are the only company to go from fragment to compound in the clinic twice,” said Dr. Jhoti. “In addition, we have a third compound that we expect to go into the clinic next year. Having identified five drug candidates in four years, it should be noted that all five compounds started as fragments. We see that as reasonable productivity.”
SGX Pharmaceuticals (www.sgxpharma.com) has also developed a fragment-based drug discovery platform that utilizes high-throughput x-ray crystallography for lead identification and optimization. Stephen K. Burley, M.D., D.Phil., CSO, talked about SGX523, a MET inhibitor that, he says, is highly selective, orally bioavailable, and intended to exploit a targeted approach to cancer treatment.
“This is a hot target. Activating MET mutations, MET gene amplification, and aberrant MET activation are implicated in a huge number of human cancers,” said Dr. Burley. The MET protein controls cell growth and motility and is thought to play an important role in metastases of many tumors.
Dr. Burley also presented SGX’ structure-guided, fragment-based approach known as FAST™ (fragments of active structures). Each member of the FAST fragment/scaffold library was selected to be amenable to rapid chemical elaboration at two or three points of chemical diversity using parallel organic synthesis.
Initial lead optimization involves using knowledge of the cocrystal structure of the target-fragment complex and advanced computational chemistry tools to guide synthesis of small-focused linear (1-D) libraries. These linearly elaborated fragments/scaffolds are then evaluated with in vitro biochemical and cellular assays and cocrystal structure determinations. Active compound series are prioritized for further medicinal chemistry and compound development efforts using the results of in vitro and in vivo ADME and toxicology studies.
“Our structure-based drug discovery approach to MET yielded SGX523, which has exquisite selectivity for MET over all other protein kinases tested. Not only is it orally bioavailable and of low molecular weight,” said Dr. Burley, “but it also has excellent ADME characteristics and in vitro safety properties, covers virtually all of the clinically characterized MET mutants, and was well-tolerated in animal studies.” SGX expects to file an IND for SGX523 by Q1 2008, and begin clinical studies shortly thereafter. “We believe this compound has the potential to be a best-in-class MET inhibitor.”