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 lead to constitutively active IRAK complex driving the 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.
IRAK4 is, in addition, a key target for the treatment of inflammatory disorders including rheumatoid arthritis, inflammatory bowel disease (IBD), lupus and gout.
IRAK4 is an idiosyncratic kinase where selectivity and cellular potency has been very challenging to achieve. Nimbus has generated multiple lead series that address both these attributes. Importantly, the Nimbus approach provides a clear rationale for selectivity and a path to optimization.