In February, the Johnson & Johnson unit Janssen Biotech Inc. announced a collaboration with Araxes Pharma LLC, a start-up predicated on work out of the University of California, San Francisco (UCSF). [See Deal] Now, with a publication in Nature, further details on the company have been revealed.

Araxes is going after tumors with mutant Ras protein, tackling one of the most intractable drug targets in cancer. Mutations in the K-Ras enzyme, for example, are the most common activating lesions in cancer and are generally associated with poor response to standard therapies.

“We are trying to take approaches that other people are not,” says UCSF’s Kevan Shokat, PhD, an Araxes co-founder. “Basically, we are looking for chemical opportunities that other people might have missed.” The Nature paper describes a discovery in Shokat’s group at UCSF that forms the basis for one of Araxes’ inaugural programs. It shows how small-molecule inhibitors of K-Ras irreversibly bind to a common K-Ras mutation away from its active site, and how this so-called allosteric binding changes the catalytic properties of the enzyme and disrupts cancer-causing activity.

The starting point came three years ago, when the Shokat group began screening cysteine-reactive small molecules against K-Ras (G12C). (The G12C mutation results in an amino acid substitution at position 12 in K-Ras, from a glycine to a cysteine.) G12C is the third most frequent K-Ras mutation and is found in just under 3% of all cancers, according to Shokat.

Cross-reactivity with the wild-type form of Ras is one of the historic difficulties in cysteine-based targeting of this family of signal transduction proteins, but the researchers identified fragments that reacted with G12C but not the wild-type form of K-Ras, which contains three cysteine residues. They chose one candidate fragment on which to make modifications, enhanced its binding to G12C, and with that model molecule now in hand, attempted to make a co-crystal structure to be able to pursue structure-based design. They succeeded, and discovered the compound was bound to a fully-formed pocket in K-Ras (G12C) that was not apparent in other published structures of the molecule.

The presence of this newly discovered binding region, which they called the switch II pocket (S-IIP), confirmed to the researchers the possibility they were pursuing a novel path for K-Ras-related drug discovery, which to that point had been problematic.

“We had compounds that were binding specifically, but they weren’t binding very strongly, even for the kind of approach [we were using],” Shokat says. “We had tried to make modifications and they weren’t really working, and that’s usually a sign that there’s not a real pocket.” Shokat saw the crystal structure in mid-December 2011. “I spent the whole Christmas break poring over that crystal structure, looking at it in different ways,” he says. “Then we knew we had something.” Ultimately, his lab validated the general proposition that S-IIP binding compounds are irreversible, mutant-specific inhibitors of Ras function. Further, initial evaluations of these compounds in lung cancer cell lines suggested allele-specific impairment of K-Ras.

The discoveries quickly led to the formation of Araxes.

Shokat, along with current Araxes executives Troy Wilson, PhD (president and CEO), Yi Lu, PhD (CSO), and Pingda Ren, PhD (SVP, chemistry), had previously co-founded Intellikine Inc., which was acquired in early 2012 by Takeda Pharmaceutical Co. Ltd.’s Takeda Oncology unit. [See Deal] (See [A#28120103001].) They then went on to form Wellspring Biosciences, an incubator focused on the discovery and development of drugs targeting signal transduction networks. Araxes is the first publicly announced Wellspring affiliate.

When Takeda gobbled up Intellikine, Shokat’s UCSF group had done a third to a half of what’s reported in the Nature paper. “We said we’ve got an inkling that this might be a druggable pocket, and K-Ras is as important as the Pi3 kinase pathway we worked on at Intellikine.” With the chemists and biologists formerly at Intellikine, Araxes was able to hit the ground running.

Araxes is taking “a diversity of approaches to different pockets and different post-translational modifications and different allosteric strategies,” Shokat says. “We are being very chemistry versatile but pathway focused.” In addition to the S-IIP inhibitor work, the start-up is exploring other ways to target Ras, as well as looking at other ways to target points in the Ras pathway. “Some of those others are more in the literature, but we feel we have an insight into those targets as well,” Shokat says. Although he is being tight-lipped about Araxes' other programs, one is a covalent strategy also relying on a cysteine.

Janssen has licensed the early IP describing the S-IIP pocket and the strategy of going after the G12C allele. Araxes will take S-IIP compounds through proof-of-concept trials, after which Janssen can opt into the program.

Next on Shokat’s to-do list is improving the understanding the effect of the K-Ras inhibitors has on cell signaling. Separate from Araxes, his lab also has started projects around targeting other alleles and other strategies for targeting Ras proteins.

Shokat is also proud of the care his group took to do the early structure-based work first, which may have influenced Janssen’s decision to collaborate early.

Academics are often pushed to take compounds through and have them show the effect that you expect of them, he says. “There’s a lot of talk in the literature now about how a lot of things in academia are not reproducible and drug companies can’t take them and run with them,” he points out. “Our paper is a little different in the sense that we concentrated on doing the initial chemistry, the structural biology and the biochemical efficacy really well.” Sometimes, what’s more important is to do the early work very carefully, he says. “Otherwise, compounds might go all the way to cell and animal data but the strength of the data goes down and down as you go later, because nobody had the time to do the necessary chemistry.”

UCSF Start-Up Shows Off Its Approach To K-Ras Inhibition

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