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
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.