Third Rock Ventures and the Column Group are investing $25.1 million in a fresh bet on Nurix Inc., a San Francisco-based start-up planning to use small molecules to leverage control of ubiquitin proteasome system (UPS) to attack cancer and other diseases. The series B round builds on a $6.2 million seed financing led by the same investors in 2012.

The UPS is a regulatory pathway that directs protein degradation, suggesting it may be an ideal avenue for promoting the breakdown of oncogenes or shielding tumor suppressors from destruction, said Mark Gallop, the company's chief scientific officer. Nurix's first target, the ligase E3, is the last in a series of three enzymes that control the placement of ubiquitin onto a protein, making it a key regulator in determining proteins' fates.

So far, the company has identified a group of small molecules that modulate E3 that it's optimizing on its way to selecting a lead development compound, interim Nurix CEO and Third Rock partner Mark Goldsmith told BioWorld Today.

With its new funding, Nurix's team will use the knowledge it has developed around modulating E3 and the feedback provided by protein crystallography and integrated computational modeling to identify new targets in the E3 ligase family and build a discovery engine for use in identifying additional promising molecules. Its toolkit reveals the interactions between enzymes (E2, a ubiquitin-conjugating enzyme, and E3s) and substrates, revealing key areas where small molecule can disrupt or enhance protein-protein interactions.

The company is starting with cancer first because the application of UPS modulation in oncology has already been validated by the pioneering proteasome inhibitors Velcade (bortezomib, Millennium: the Takeda Oncology Co.), the first to be approved by the FDA, and Kyprolis (carfilzomib, Amgen Inc.) "By moving upstream into the regulatory realm of this pathway, we think there's an opportunity to be more selective," said Goldsmith.

Nurix was founded by three experts in the UPS field: John Kuriyan, a professor of molecular and cell biology and of chemistry at the University of California, Berkeley; Michael Rapé, a professor of cell and developmental biology at UC Berkeley; and Arthur Weiss, a professor at the University of California San Francisco. All three are investigators at Howard Hughes Medical Institute. As the small company settles into new lab space adjacent to the UC San Francisco Misson Bay campus, it has nearly 10 employees and plans to grow both its scientific and executive management team throughout 2014.

In addition to Goldsmith, former CEO and current chairman of Cambridge, Mass.-based Constellation Pharmaceuticals Inc., Column Group managing partner David Goeddel sits on Nurix's board. Goeddel, once a star scientist at Genentech Inc., part of Roche AG, co-founded and led Tularik Inc., which was acquired by Amgen in May 2004. (See BioWorld Today, May 30, 2004.)

Column Group partner Tim Kutzkey is serving as Nurix's interim president and also sits on its board.

The Nurix team is excited about the UPS space work partly because the field has progressed significantly in the past few years, with a rising number of publications around UPS, said Goldsmith. Discovery and clinical development work in the space is growing, too, with 19 small-molecule proteasome inhibitors in discovery for cancer indications, according to Thomson Reuters Cortellis. (See the chart below.)

"Our understanding of the fundamental biology of the ubiquitin proteasome system and its role in select cancers and other diseases has grown significantly and continues to expand rapidly," he said. A January 2014 article in Science even identified previously unknown E3 activity in a blockbuster: Celgene Corp.'s Revlimid (lenalidomide).

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