Discovery of Highly Potent and Selective IRAK1 Degraders to Probe Scaffolding Functions of IRAK1 in ABC DLBCL

MyD88 gene mutation has been identified as one of the most prevalent
driver mutations in the activated B-cell-like diffuse large B-cell
lymphoma (ABC DLBCL). The published literature suggests that interleukin-1
receptor-associated kinase 1 (IRAK1) is an essential gene for ABC
DLBCL harboring MyD88 mutation. Importantly, the scaffolding function
of IRAK1, rather than its kinase activity, is required for tumor cell
survival. Herein, we present our design, synthesis, and biological
evaluation of a novel series of potent and selective IRAK1 degraders.
One of the most potent compounds, Degrader-3 (JNJ-1013), effectively degraded cellular IRAK1 protein with a DC50 of 3 nM in HBL-1 cells. Furthermore, JNJ-1013 potently
inhibited IRAK1 downstream signaling pathways and demonstrated strong
anti-proliferative effects in ABC DLBCL cells with MyD88 mutation.
This work suggests that IRAK1 degraders have the potential for treating
cancers that are dependent on the IRAK1 scaffolding function.