Fragment Based Lead Discovery San Diego 2011

Zenobia Therapeutics hosted a one-day FBLD meeting in San Diego last Friday. It was a very full day of seven talks and plenty of informal discussion, with both lunch and happy-hour on a rooftop terrace overlooking the ocean. I’ll try to give some flavor of the event below – those of you who were there, please chime in with your own impressions.

In the first talk of the day, Michael Recht of Xerox’s PARC discussed the construction and use of array-based nanocalorimetry devices, which analyze samples as small as a couple hundred nanoliters. Although conceptually related to isothermal titration calorimetry, the scale of nanocalorimetry makes direct measurement of binding enthalpy difficult. However, the devices are well-suited to measuring the heat output from enzymatic reactions, thus allowing detailed study of enzyme kinetics and inhibitor characterization (see here for a full description and here for a review, both open-access).

Maurizio Pellecchia of the Sanford-Burnham Medical Research Institute gave a wide-ranging talk with the common theme of NMR as an enabling method. In particular he noted that, due to its low protein requirements, ILOE (which we’ve written about previously) could be considered the “homeopathy of NMR;” a recent paper in J. Med. Chem. describes its application to generate hits against Bcl-family proteins. He used a different NMR technique to discover a potent and selective JNK inhibitor that binds in both the ATP and substrate binding sites. On a completely different topic, Maurizio noted that roughly one-third of drug targets contain metals, prompting the construction of a fragment-library designed with metal-chelation in mind, a strategy we’ve written about previously (see also here). Many of these techniques and libraries have now been licensed into a new company, AnCoreX Therapeutics, founded by Maurizio.

Schrödinger was a major sponsor of the meeting, and company scientist Kathryn Loving gave a good overview of the potential of their suite of software tools for fragment-based lead discovery. After lunch I presented a PDK1 story (see here) as well as applications of Carmot’s Chemotype Evolution, and Michelle Arkin from UCSF discussed some of the capabilities of the university’s Small Molecule Discovery Center, with special focus on protein activators and protein-protein disruptors.

Tony Giannetti of Genentech gave a nice presentation on caspase-6 inhibitors and also discussed the power of SPR, a topic on which he’s written extensively. He noted that as long as one is careful about conducting the experiment, the number of promiscuous or non-specific binders found by SPR tends to be less than the number of true hits – he described the former as “a managed headache.”

Tony is in the enviable position of having screened numerous targets using the same platform, allowing him to do some very interesting data mining. One phenomenon that we’ve previously commented on is the fact that, across multiple companies, only about a third of fragments hit in one or more screens, and Roche is no exception (36% across 13 screens). With the merger of Genentech and Roche now complete, Tony has been able to compare the fragment libraries assembled separately at each institution. Interestingly, although they contain < 5% common fragments and < 10% similar fragments, the libraries are, by broad measurements such as size or lipophilicity, statistically indistinguishable. However, the hits from the Roche collection seem to have higher ligand efficiencies. Also, the most potent binders tend to have 13-17 atoms, with the most ligand-efficient molecules generally having a molecular weight < 200. Finally, there has been a lot of recent discussion on making fragments less flat (aromatic) and more three-dimensional (often aliphatic). However, as I predicted 2 years ago, one needs to be cautious: it turns out that hits were actually enriched for flatter fragments, although Tony did mention that most of the screens were against kinases, which may be particularly “flatophilic”.

Vicki Nienaber, founder and president of Zenobia, closed the conference by discussing the potential for fragment-based approaches to tackle diseases of the central nervous system (CNS). The rationale is that, since CNS drugs need to be small to cross the blood-brain-barrier, it pays to start with fragments. Indeed, Zenobia’s fragment library has a molecular weight averaging just 150-175, with an upper limit of 225, which should allow them to avoid molecular obesity. Vicki described the discovery of nanomolar leads against LRRK2, a Parkinson’s disease target, and against PDE10, a Huntington’s disease target.

As far as I know this was the last face-to-face fragment event this year, but there are still several webinars this month and next, and it’s not too soon to start planning for 2012; please see here for upcoming events.

Updated: fragment events in 2011 and 2012

As 2011 winds to a close there is still one more addition to the calendar, and 2012 is shaping up nicely.

August 16 - November 15: Is your travel budget limited? Emerald Biosciences is putting together a series of free webinars related to FBLD on August 16, September 20, October 18, and November 15. If you've missed any they are all archived online.

October 21: Zenobia Therapeutics is putting together a FBLD conference in San Diego. Although just one day, there is a nice lineup of speakers, so try to make it if you can.

October 25 - November 15:  The Society for Laboratory Automation and Screening (SLAS) is holding a 4-part webinar titled "Interrogating Chemical Space — Rules, Filters, Fragment-Based Screening and Beyond," with presentations by Chris Lipinski (October 25), Mike Hann (November 1), me (November 8), and Dan Wyss (November 15).

2012

March 19-23: Keystone Symposium: Addressing the Challenges of Drug Discovery – Novel Targets, New Chemical Space and Emerging Approaches will be held in Tahoe City, CA. Although not exclusively devoted to fragments, there are many speakers I look forward to hearing.

April 17-19: Cambridge Healthtech Institute’s Seventh Annual Fragment-Based Drug Discovery will be held in San Diego. You can read impressions of this past year’s meeting here and 2010’s here.

August 19-23: The 244th National ACS meeting will be held in Philadelphia, and there will be at least one symposium on FBLD.

September 23-26: FBLD 2012, the fourth in an illustrious series of conferences, will be held in my fair city of San Francisco. This should be a biggy – the first such event in the Bay Area (and the weather in September is usually decent too). You can read impressions of FBLD 2010 and FBLD 2009.

Know of anything else? Organizing a fragment event? Let us know and we’ll get the word out.

Fragment-based events in 2011 and 2012

If you missed the fragment events earlier this year there is still one late addition to the calendar as well as some webinars. And it’s not too soon to be thinking about 2012!

August 16: Is your travel budget limited? Emerald Biosciences is putting together a series of free webinars related to FBLD on August 16, September 20, October 18, and November 15.

October 21: Zenobia Therapeutics is putting together a FBLD conference in San Diego. Although just one day, there is a nice lineup of speakers, so try to make it if you can.

2012

March 19-23: Keystone Symposium: Addressing the Challenges of Drug Discovery – Novel Targets, New Chemical Space and Emerging Approaches will be held in Tahoe City, CA. Although not exclusively devoted to fragments, there are many speakers I look forward to hearing.

April 17-19: Cambridge Healthtech Institute’s Seventh Annual Fragment-Based Drug Discovery will be held in San Diego. You can read impressions of this past year’s meeting here and 2010’s here.

September 23-26: FBLD 2012, the fourth in an illustrious series of conferences, will be held in my fair city of San Francisco. This should be a biggy – the first such event in the Bay Area (and the weather in September is usually decent too). You can read impressions of FBLD 2010 and FBLD 2009.

Know of anything else? Organizing a fragment event? Let us know and we’ll get the word out.

Fragment-based conferences in 2011

As 2010 winds to a close, it’s time to start planning for 2011. As in previous years, fragment events seem to cluster in the first half of the year, so start planning now!

February 21-22: SMi’s 10th Annual Advances & Progress in Drug Design Conference will be held in London, and has a number of fragment-based talks. There is also a separate half-day post-conference workshop on the topic on February 23.

February 23-25: CHI’s Molecular Medicine Tri-Conference will again be held in my beautiful city of San Francisco, with a program on medicinal chemistry that includes a fragment section. Notes on this past year’s meeting can be found here.

March 7-8: Fragments 2011, the Third RSC-BMCS Fragment-based Drug Discovery meeting, will be held in Stevenage, UK. This is a biennial event; the last was in Alderley Park in 2009 (you can read about it here and here). Registration is now open, as is a call for posters through January 31.

April 12-13: Cambridge Healthtech Institute’s Sixth Annual Fragment-Based Drug Discovery will be held in San Diego, with at least one pre-conference short course on the topic on April 11. You can read impressions of this past year’s meeting here.

Know of anything else? Organizing a fragment event? Let us know and we’ll get the word out.