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Navire launches to clog cancer proteins with ‘molecular glue’

With $30 million from BridgeBio Pharma, biotech firm will develop small-molecule inhibitors of the tyrosine phosphatase SHP2

by Ryan Cross
October 4, 2017 | A version of this story appeared in Volume 95, Issue 40

Credit: New York University
Benjamin Neel has studied tyrosine phosphatase proteins, such as SHP2, for 25 years.
A photo of NYU professor Benjamin Neel
Credit: New York University
Benjamin Neel has studied tyrosine phosphatase proteins, such as SHP2, for 25 years.

BridgeBio Pharma and the University of Texas MD Anderson Cancer Center announced the launch of a $30 million BridgeBio-backed subsidiary called Navire Pharma today. Navire will focus on developing small-molecule inhibitors of an enzyme called SHP2, implicated in a swathe of cancers.

“I’ve been working on this protein for longer than I want to admit, so this is exciting,” says Benjamin G. Neel, director of New York University’s Perlmutter Cancer Center. SHP2 belongs to the tyrosine phosphatase family of proteins, which help relay chemical messages controlling cell growth and division. Neel has studied the proteins since 1992, and is now contributing his expertise to Navire as scientific cofounder and chair of the scientific advisory board.

MD Anderson is contributing its SHP2 inhibitors to the collaboration and will continue to spearhead studies until a compound is ready for human trials. Navire will take the reins at that point, anticipated around the end of 2018 or early 2019.

The SHP2-inhibitor compounds won’t target tumors that have SHP2 mutations. But since SHP2 lies in the center of a pathway for promoting cell growth and division, researchers think that blocking its activity could halt the growth of tumors spurred by malfunctions in the pathway in front of or behind SHP2. “We are interested in genetically driven tumors and are agnostic to where those tumors are,” explains Navire CEO Shafique Virani, who was previously a vice president at Genentech.

“Tyrosine phosphatases have been viewed as a graveyard of drug development for decades,” Neel says. One reason, he says, is that previous compounds targeting SHP2’s highly charged active site don’t readily enter cells. But in 2016, chemists at Novartis reported a compound that fills a tunnel that forms during SHP2’s closed or inactive state. Neel says the Novartis compound works like “molecular glue,” holding three enzymatic domains of SHP2 together and turning off its activity. Navire’s compounds follow a similar approach.

BridgeBio was formed in 2015 but remained in stealth until January 2017. Its strategy is to launch laser-focused subsidiaries, rather than manage everything under one portfolio. That gives Navire “a tremendous amount of freedom going forward,” Virani says.

Navire might pursue partnerships in, for example, the immuno-oncology field. Activation of SHP2 also turns down T cell activity—through the drug target PD-1—reducing the immune system’s ability to fight tumors. Inhibiting SHP2 could thus have an added effect of removing the brakes on the immune system.

Neel is hopeful that the same strategy used to target SHP2 could be applied to discovering drugs for other tyrosine phosphatases. “I think we will see a rebirth of targeting phosphatases for many diseases.” Neel says.



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