12:00 AM
Dec 24, 2012
 |  BioCentury  |  Product Development

Nimbus' lymphoma watershed

Nimbus solves IRAK4 puzzle for mutation-defined subtypes of B cell lymphomas

It has taken Nimbus Discovery LLC just three years from its founding to identify lead inhibitors against the historically intractable target IRAK4 to treat autoimmune disease and cancer. This month the company presented preclinical data showing that combining IRAK4 and Btk inhibitors had a synergistic effect in mutation-defined subtypes of two B cell lymphomas.

IL-1 receptor-associated kinase 4 (IRAK4) plays a role in innate immune signaling and has been implicated in autoimmune diseases such as rheumatoid arthritis (RA), psoriasis and gout. In 2011, a team at the National Cancer Institute showed for the first time that IRAK4 inhibitors had potential in B cell lymphomas (see SciBX: Science-Business eXchange, Jan. 13, 2011).

While the protein's structure was solved over a decade ago, the development of potent and selective inhibitors has been slow because of a structural feature that distinguishes IRAK proteins from other kinases: a tyrosine residue that blocks the back pocket of the ATP-binding site.

This "gatekeeper" tyrosine leaves only a wide, shallow binding region on the outside of the pocket accessible to potential inhibitors, CSO Rosana Kapeller told BioCentury.

"If you apply a high throughput screening library to this target, you achieve very low hit rates and...

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