Just say yes to druggable targets

The idea for Vividion’s cutting-edge platform was spun out of the lab of Benjamin F. Cravatt III, professor and co-chair for the Department of Molecular Medicine of the Skaggs Institute for Chemical Biology at The Scripps Research Institute. Cravatt led the charge along with academic chemists Dr. Phil Baran and Dr. Jin-Quan Yu at TSRI, who built a system for testing chemical drugs against proteins in human cells. The scientists had a suspicion that disrupting proteins could have an effect on disease.

“The Vividion platform represents the most broadly applicable platform technology to come out of the Cravatt lab,” says Tom Daniel, Vividion executive chairman and former president of research and early development of Celgene. Cravatt “has been creating innovations in the field of chemical biology for more than 20 years.” He notes that Cravatt’s work has “consistently emphasized the value of evaluating protein function, and small-molecule protein interactions in native biological systems.”

Also, Cravatt has founded two previous companies, ActivX Biosciences, and Abide Therapeutics, each based on unique and powerful chemical biology approaches.

The first platform for proteomics-wide ligand and target discovery represents a “revolutionary approach” to target and drug discovery that will “dramatically expand and redefine the types of targets that can be considered as druggable,” according to Daniel.

These druggable proteomes include proteins—such as enzymes and receptors—that are traditionally considered as drug development candidates because they have binding sites that affect an easily measurable activity, Daniel says, adding that many other protein classes—adapter proteins and transcription factors among them—either do not have a clearly measurable activity and/or a known binding site amenable to small-molecule binding. Thus, they are not typically considered for drug discovery and development efforts.

Vividion’s synthetic chemistry approaches are combined with novel proteomic methodologies to enable comprehensive screening of proprietary small-molecule/fragment libraries against not only the entire repertoire of proteins in a cellular system but also any pockets on these proteins that can support specific binding events, Daniel says, adding that traditional drug screening approaches test libraries of small molecules that often represent a fairly limited range of shapes and features (due to limitations of standard synthetic methodologies), against a specific site on an individual target protein.

This can be conceptualized as looking for the intersection (or a liganding event) between a limited chemical space with a single biological hypothesis, he explains, and the Vividion approach is to look for all points of intersection between a much broader chemical space with the entire constellation of biological targets in a single screen. Along with the unprecedented scope of these screens, the Vividion approach allows these screens to be conducted directly in biological systems where critical structural modifications and protein interactions are preserved.

The platform expands the definition of druggability on mechanisms in serious illnesses, while delivering new routes to address highly validated disease targets, Daniel maintains. He notes that Vividion researchers believe that any protein has the potential to be drugged with the Vividion platform and therefore they are using a rigorous human biology filter for target selection and prioritization. However, Vividion is not disclosing a focus on any specific type of disease as yet—Daniel says that Vividion’s platform is “completely agnostic as to therapeutic space.”

While Vividion is focused on becoming an independent and successful drug development entity, he adds, there is a recognition that the implications of the new company’s platform are much broader than a single company can fully realize. As such, Vividion is already beginning discussions to establish a key strategic relationship with a biotech/pharma partner.

Kristina Burow, managing director at ARCH, says, “The team at Vividion Therapeutics has created a novel platform based on chemical proteomics and modern synthetic chemistry that will radically expand the druggability of the human proteome.”