Further proof that targeted protein degradation is finding its moment in the spotlight arrived with word that Gilead Sciences Inc. has agreed to pay Nurix Therapeutics Inc. $45 million up front and as much as $2.3 billion in milestones to discover, develop and commercialize several new drugs for cancer and other challenging diseases. The multiyear collaboration is aimed at identifying new agents that leverage E3 ligases to induce degradation of specified targets, Nurix's specialty and the centerpiece of its 2015 deal with Celgene Corp. (See BioWorld, Sept. 17, 2015.)

Foster City, Calif.-based Gilead will have an option to license candidates directed to up to five targets resulting from the work while Nurix will retain the option to co-develop and co-detail up to two programs in the U.S. For those programs that San Francisco-based Nurix opts to co-develop and co-detail, the parties will split development costs as well as profits and losses 50-50 for the U.S., and Nurix will be eligible to receive royalties on ex-U.S. sales and reduced milestone payments.

Nurix CEO Arthur Sands told BioWorld that the power of the deal is that "we're able to explore novel targets with this new technology, targeted protein degradation, with the expertise of a partner in new therapeutic areas." The financials – up to $2.3 billion in research, preclinical, clinical, regulatory and commercialization milestones, as well as up to low double-digit tiered royalties on net sales – are "a marker of the strategic importance of the deal to both parties," enabling each to put significant resources behind their collaboration, he said.

Primed for discovery

"The field is primed to discover new drugs," said Alessio Ciulli, a professor at Scotland's University of Dundee, whose lab has done pioneering work on PROTAC (PROteolysis TArgeting Chimeric) molecules, an approach to harnessing the ubiquitin-proteasome system, from Arvinas Inc., that is adjacent to Nurix's method. Ciulli, who has also worked with Nurix, told BioWorld the approaches are, in principle, disease agnostic. "That's the really exciting power of this new modality."

Degraders are largely similar across technology platforms, featuring a binder to the protein of interest, a linker and a binder to ubiquitin ligase. Put together, that single molecule binds to the protein of interest, tagging it with the ubiquitin ligase to trigger its destruction. But the new deal between Gilead and Nurix shows that key differences in approach can still lead to differentiation in the space.

"We've been interested in the protein degrader approach for a number of years and following the field as it matured," Linda Higgins, senior vice president of biology at Gilead, told BioWorld. "What ultimately attracted us to select Nurix was their deep expertise in the biology of E3 ligases, understanding that from a number of different angles, including the degradation angle."

Gilead was drawn to work Nurix has invested in building out a DNA-encoded library of small molecules particularly designed for identifying good starting bindable chemical matter for degraders, she said. Nurix's has also identified 16 additional ligases not previously explored for drug development, a line of work that may open up new areas of access for protein degradation.

Though oncology drug development will clearly be one use for the technology, Higgins said Gilead also sees potential for its application "across targets that are difficult to address using more conventional small-molecule means, those that one would like to degrade because simple inhibition will not be sufficient or as good as degradation, or those that don't have a conventional small-molecule binding pocket and aren't amenable to the more conventional approaches."

A spectrum of ligases

Though neither Nurix nor Gilead have disclosed exactly which indications they plan to chase with the technology, Sands said that among them will be areas beyond oncology, immune-oncology and hematology – areas in which Nurix has worked on its own and with Celgene.

Having a spectrum of ligases that have activity in different tissues offers the ability to hit a broader spectrum of targets, and holds the promise of being more specific, too, Sands said.

Though still early in their development, PROTACs have generated significant interest from investors and, more recently, from big pharma players, with some of the earliest work sparked by the research in the lab of Yale University's Craig Crews, where Ciulli once was a visiting fellow. Fast-forwarding to 2018, Arvinas signed a potential $830 million multiyear research collaboration and license agreement with Pfizer Inc., of New York. In March of this year, Arvinas' orally bioavailable PROTAC protein degrader entered phase I. And not long after, it inked yet another deal with Bayer AG covering cardiovascular, oncological, gynecological diseases and agricultural applications.

Further work on developing PROTACs is underway at Boehringer Ingelheim GmbH, where Ciulli has been a central contributor to efforts to design bifunctional molecules that use E3 ligases to go after SMARCA2, a previously undruggable target in cancer. Earlier this month, the partners agreed to extend their collaboration to develop new medicines.