New inflammasome structure from Harvard, SMOC fodder for rational drug design

A Harvard, SMOC group is solving the structures of large complexes to inform drug discovery, starting with the inflammasome

The ability to rationally design small molecules against a highly sought after inflammasome target -- NLRP3 -- got a boost Wednesday when new structural information was published in Nature by a group from Harvard Medical School that also includes authors from SMOC Therapeutics.

The NLRP3 inflammasome has become an increasingly attractive target to treat immune-mediated diseases, as it sits atop an inflammatory cascade that triggers cytokine release and immune cell recruitment. Inhibitors of NLRP3 have been the driving factor behind at least two acquisitions in the past eight months (see “NLRP3 Early and Often”).

But what is lacking in NLRP3 inflammasome drug development is structural information, SMOC Therapeutics Inc. co-founder Hao Wu told BioCentury. He said many NLRP3 inhibitors in industry's pipeline are optimized versions of a tool compound published in a 2015 Nature paper, and/or were discovered through cellular assays rather than rational design. Wu, an investigator on the Nature study, is a professor in the department of Biological Chemistry and Molecular Pharmacology at Harvard Medical School.

“Three papers came out all demonstrating that NEK7 is absolutely required for NLRP3 activation.”

Hao Wu, Harvard

Wu’s team published the cryoEM structure of NLRP3 in complex with a more recently identified, but crucial, binding partner: NEK7.

"In 2016, three papers came out all demonstrating that NEK7 is absolutely required for NLRP3 activation," Wu said, and understanding how NEK7 interacts with and regulates the complex would fill in important gaps needed to design modulators. The three independent studies were published in Nature, Nature Immunology and the Journal of Biological Chemistry.

Wu's study, which also investigates how particular residues in the NEK7:NLRP3 interface affect the inflammasome’s function, provides a road map to find new chemical matter to inhibit or activate the complex, or further optimize existing compounds and evaluate the mechanisms through which they modulate the inflammasome, Wu said.

It also showcases early work by SMOC Therapeutics, which was founded in late 2017 with $7.5 million in seed funding to treat innate immune-driven diseases by targeting supramolecular organizing centers (SMOCs) like the NLRP3 inflammasome.

Wu and SMOC SVP of Drug Discovery Kevin Sprott declined to discuss the company’s pipeline or how it will use the information in the Nature study for a drug development program targeting the NLRP3 complex.

But, Sprott said, the study is an example of how SMOC is using its platform of biochemical, biophysical and structural techniques to enable drug development for large molecular signaling complexes that drive innate immune signaling.

The lack of structures for these have hindered the field, said Wu and Sprott.

Targets: NEK7 - NIMA-related kinase 7; NLRP3 (NALP3; CIAS1) - NLR family pyrin domain containing 3

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