Interleukin-1 Receptor-Associated Kinase 4 (IRAK4)

IRAK4 is a signaling kinase that becomes inappropriately activated in activated B-cell-like diffuse large B-cell lymphoma (ABC-DLBCL), an aggressive tumor with poor prognosis.  The only targeted therapeutic approved for the treatment of this tumor type is Rituxan®.  Recent discoveries point to a mechanistic link with IRAK4 where ~37% of these tumors contain oncogenic mutations in MYD88, an adaptor protein that interacts directly with IRAK4.  These mutations constitutively activate the IRAK complex, driving prosurvival pathways in ABC-DLBCL tumors. This genetically-defined patient population can be identified in the clinic prior to treatment, increasing the likelihood of response and creating truly personalized medicine.  Oncogenic MYD88 mutations have subsequently been identified in additional tumors, including Waldenström's Macroglobulinemia (90%+) and chronic lymphocytic leukemia (CLL).

IRAK4 is also an important target for the treatment of inflammatory disorders including rheumatoid arthritis, inflammatory bowel disease (IBD), lupus and gout.

As a result of unique structural attributes, selectivity and cellular potency have been very challenging to achieve with IRAK4.  Despite this, Nimbus has generated exquisitely selective compounds that are highly drug-like.  Importantly, the Nimbus approach has provided a clear rationale for selectivity and rapid lead optimization.

Download the poster presented by Nimbus Discovery at the 2012 American College of Rheumatology (ACR) Annual Scientific Meeting: