Vicinitas (noun), Latin
Neighborhood, nearness, proximity, vicinity
Small molecules, or synthesized chemicals, are some of our most important and most recognized drugs (think Lipitor). Despite their success, small molecules have been limited by the types of therapeutic mechanisms of action or biological target classes they can tackle. Over the past few decades, biotechnology has filled this void with new and innovative medicines: Large molecules, or therapeutic proteins, can replace missing hormones in the body like insulin; programmable medicines like CRISPR offer the tantalizing prospect of genetic cures. Yet, despite this expanding therapeutic arsenal, small molecules have remained a mainstay of medicine, making up 75 percent of all new medicines approved in the US in 2020. They can be delivered orally, are generally easier to synthesize/manufacture, and are significantly less expensive than more complex medicines like gene therapies. All things being equal, a small molecule is preferred over other therapeutic modalities — if it can get the job done.
New tools have ushered in a sharper, more precise era of medicine, increasingly giving us abilities to create small molecules with new superpowers to tackle higher-hanging fruit like previously “undruggable” targets. DNA-encoded libraries bring ever-greater diversity to explore new chemical space. Artificial intelligence is helping generate new target insights and design better molecules. Scientists are even developing small molecules with entirely new functionalities, such as PROTACs. PROTACs are bi-functional small molecules that bring together two proteins to tag (ubiquitinate) a target protein for degradation and disposal. We’re in a second golden age for small molecules; scientists are finding novel ways to build on and expand on their strengths — they’re teaching good dogs new tricks.
“This is really cool!” My partner Becky Pferdehirt had just shared the link to a recent paper just posted to bioRxiv on an internal team Slack channel and added a few choice emojis to show her excitement. The paper demonstrated the first ever design and use of a bi-functional small molecule to recruit a protein (OTUB1) that removes ubiquitination tags from proteins to keep targeted proteins from being degraded. These compounds, dubbed DUBTACs, are in essence the mirror image of PROTACs – instead of degradation, they promote targeted protein stabilization. Many cancers and monogenic diseases are caused by specific proteins that are abnormally degraded and lost from the cell. By stabilizing these proteins, DUBTACs could become an entirely novel way to treat disease – and all with a small molecule!
“This should be a company; we’ve got to talk to Dan ASAP,” insisted Becky. Dan Nomura is a professor of chemical biology at UC Berkeley, and a repeat biotech founder; he was thinking the same thing. His lab had developed the DUBTAC platform as part of a unique academic-industry collaboration with Novartis Institutes for BioMedical Research (NIBR). Our partner Judy Savitskaya, who, like Becky, holds a PhD from Berkeley, knew Dan and organized a meeting. Over a patio dinner that went long into a chilly Northern California night, Dan painted his vision and ambitions for a DUBTAC newco. I then met with Jay Bradner, president of NIBR, in Cambridge. Over beers, chicharrón and too many tacos, Jay also expressed his enthusiasm for DUBTACs and desire to explore a “creative experiment” to nurture this innovation outside of Novartis’ four walls.
It wasn’t long before Becky and I started working in earnest with Dan, Cam Wheeler and our friends at Deerfield, and the NIBR team to lay down the initial foundation for Vicinitas. Soon thereafter, biotech executive and Celgene alum George Golumbeski and the Droia team joined our company-building effort and we were able to attract seasoned drug-hunter Dan Marquess as chief scientific officer, Joe Budman as VP of biology, and assemble a visionary scientific advisory board. Vicinitas was formally spun-out from the academic-industry collaboration between the Novartis Institutes for BioMedical Research and the University of California, Berkeley and is launching with a $65 million Series A financing to build the leading protein stabilization platform based on its proprietary DUBTAC technology. a16z is thrilled to co-lead this financing with Deerfield, with participation from Droia, GV, The Mark Foundation for Cancer Research and the Berkeley Catalyst Fund.