Targeted Degradation Of Irak4 Protein Via Heterobifunctional Small Molecules For Treatment Of Myd88 Mutant Lymphoma

Recurrent mutations in the scaffolding protein MYD88 are present in 30-40% of activated B cell diffuse lymphocytic B cell lymphoma (ABC-DLBCL)(Ngo et al. Nature 2011). MYD88 links activated interleukin 1 receptor (IL1R) and Toll-like receptors (TLRs) to downstream effectors by nucleating assembly of the Myddosome, a multi-protein complex containing MYD88, the protein kinases IRAK4 and IRAK1 and the pseudokinase IRAK2, via oligomerization of the N-terminal Death Domains in each of these proteins (Motshwene et al. JBC 2009; Lin, Lo and Wu. Nature 2010). The most prevalent MYD88 mutation, L265P, constitutively activates assembly of the Myddosome, causing IRAK4-dependent NFκB and MAP kinase signaling and leading to lymphoma survival and proliferation (Ngo et al. Nature 2011).