MyD88 dimerization inhibitors for targeting Diffuse Large B-cell Lymphomas

Abstract

Abstract A recurring single amino acid somatic mutation associated with human diffuse large B cell lymphomas (DLBCLs), correlates with tumor cell proliferation and survival involving spontaneous and sustained activation of MyD88-dependent NF-κB and Janus Kinase (JAK) signaling pathways. MyD88 acts as a central signaling adapter for mediating innate and cytokine driven inflammation for the Interleukin-1 (IL-1R) and Toll-like receptors (TLRs). Computer aided molecular modeling of MyD88 and in silico screening have identified and functionally characterized MyD88 specific small molecule compounds shown to protect against Staphylococcal enterotoxin B (SEB) induced death in animal models. We hypothesize that MyD88 specific small molecule compounds may also be useful in treating DLBCLs bearing the oncogenic mutation MYD88L265P. Using in vitro and in vivo studies we evaluate MyD88 specific small molecule compounds for the ability to inhibit tumor cell proliferation and signaling in human patient cancer cells OCI Ly3 bearing the oncogenic mutation MYD88 L265P and OCI Ly19 DLBCLs. Previously we identified differences in the ability of MyD88 small molecule compounds to inhibit cell proliferation in activated human B cell lymphoma cells bearing the MyD88 L265P mutation. We now correlate these differences with a reduction of MyD88 interaction with IRAK in small molecule treated OCI-Ly3 cells bearing the MYD88 L265P mutation in comparison to OCI-Ly19 (wt-MyD88) and treated controls, as measured by CoIP. We continue to characterize MyD88 specific small molecule compounds that target MyD88 dimerization for their ability to reduce MyD88 containing signaling complexes in DLBCLs bearing MYD88 L265P mutation.