Genentech & UCSF Library Selection - CDD Webinar Video
CDD's May Town Hall Webinar explored how the selection of optimal chemical libraries can improve the drug discovery process.
Guided by a distinguished panel of speakers, this Town Hall style webinar challenged our panelists, as well as the audience, to think hard about what should be included in an optimal small molecule library and to consider what would be “universally desirable” screening molecules.
Click below to view the webinar recording:
CDD was joined in the discussion by:
Michelle Arkin, Associate Professor, Pharmaceutical Chemistry – Director, Biology, Small Molecule Discovery Center – University of California, San Francisco
Nick Skelton, Principal Scientist – Genentech
CDD sends an extremely grateful THANK YOU to these panelists - we appreciate your contributions in this very successful webinar!
A number of great questions were posted by the attendees during this webinar. Unfortunately, time did not permit the panelists to answer every one. So here are the remaining questions and answers not covered in the above recording.
Q: Are covalent inhibitors the next generation of drugs? What covalent libraries do you have in your screening deck, what electrophiles?
A: There is definitely increasing interest in the use of covalent modifiers as drugs following the recent approval of several such compounds. Genentech is just starting to consider such compounds in our library. They are kept on separate plates from the main library and only screened for specific projects that have an interest in a covalent modification strategy. So far we have focused on irreversible warheads with relatively low reactivity.
Q: To Nick: I am interested in Genentech's approach to the "In Between" library - are these by design structurally-related to their fragments or HTS compounds?
A: These compounds were initially selected as a diverse selection of commercially available compounds that met certain property-based criteria with an emphasis on maximizing the number of ring types present. In many cases, these core ring systems are also exemplified in our fragment and lead-like libraries. As we have grown our library, once a specific scaffold of interest is identified, we have tried to select examples that might be appropriate for our fragment, in-between and lead-like libraries.
Q: How is it different working on libraries and SAR activities when everyone is in one group versus collaborating between organizations?
A: Many of Genentech's projects involve collaborations with other organizations for the hit and lead optimization (the "SAR" part of your question). This places a big emphasis on setting up infrastructure such that all members of the collaboration have access to the most current data. We now have a pretty robust process in place but it did take significant effort to establish. Besides making the data available, being proactive about communication plays a big role in making sure that everyone on the team can provide input, and making sure that efforts are not duplicated.
Q: Do you use data from later stages in the discovery and development continuum to refine your approach to library acquisition/creation?
A: We definitely use information obtained during the hit and lead optimization stages to influence the types of molecules that we add into the library (e.g. avoiding high molecular weight, high cLogP compounds as experience has shown that they often have low solubility). More general consideration of the types of targets in the portfolio is a bigger driver for choosing the types of molecules that we want to bring into the library.
Q: Where does structure based drug design come into your drug discovery paradigm? What new structure based drug design capabilities have you added (are you adding) to your arsenal?
A: We always try to structurally enable our drug discovery projects, but this effort does not directly influence our selection of compounds for the screening library. In the area of fragment-based drug discovery, where structure determination is a key part of the follow up process, we do make sure that the compounds in this part of our library have high solubility to allow high-concentration, crystal-soaking experiments.
Q: What can a chemical vendor do catch your interest in chemical libraries?
Since chemistry space is so vast, having some hypothesis (perhaps even with data) on why a particular set of compounds might be of interest in drug discovery can go a long way towards making them more attractive to add into our library.
If you enjoyed this Town Hall PPP webinar, be sure to check the CDD Website for information on our Fall Webinar featuring Scott Snyder from Evotec.
We thank the sponsor of this webinar, Mark Parisi from Asinex, which provides a number of public and private libraries within CDD Vault.