The academic setting provides unique opportunities to drug discovery scientists, as well as some challenges, compared to the more traditional industrial or biotech models. Characteristics of a university setting not usually associated with pharma are the ability to pursue high risk projects, a depth of expertise, infrastructure and capabilities in focused areas, and the willingness to pause to follow intriguing scientific questions. This talk will highlight two drug discovery projects – one targeting cancer, the other acute kidney injury - that took advantage of the unique characteristics of an academic drug discovery environment. Through the National Cancer Institute’s Chemical Biology Consortium, a team of scientists representing multiple institutions designed and optimized novel allosteric inhibitors of the AAA ATPase p97 (VCP), an exciting, emerging target in cancer. We solved the first high-resolution structure of p97 bound to an inhibitor using cryo-electron microscopy, and further developed refined binding models of these molecules. This exercise led to the observation of a previously unrecognized protein motif, a bis-threonine turnstile. The team’s efforts provided not only starting points for the development of new experimental therapeutics, but also valuable tool molecules that are being used to decipher the complex biological pathways regulated by p97 activity.<br/>In a second project, we relied on expertise in developmental biology, nephrology and medicinal chemistry to identify and optimize small molecules that have the potential to treat acute kidney injury, a condition for which there is no effective therapy, and for which specific therapeutic targets are elusive. The dependence on zebrafish embryo screening necessitated that we develop a set of “Lipinksi rules for zebrafish” in order to interpret SAR data. Compounds developed in this project exhibit excellent pharmacokinetic properties, and have the potential to treat this very challenging condition.<br/>While on the surface very different, both projects exploit the uniqueness of the academic drug discovery environment – they are relatively high risk, rely on a depth of expertise, and have the potential to deliver not only valuable therapeutics for difficult to treat diseases, but also basic scientific knowledge to the biomedical community.

Academic drug discovery: Playing to the strengths to address challenging targets and unmet medical needs in cancer and acute kidney injury

2019 Fall National Meeting

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