Targeting of Diffuse Large B-cell Lymphomas using MyD88 small molecule inhibitors

Abstract

Abstract A mutation associated with nearly 1/3 of human diffuse large B cell lymphomas (DLBCLs) has been identified within MyD88. This mutation correlates with tumor cell proliferation and survival involving spontaneous and sustained activation of NF-κB signaling. MyD88 is a central signaling adapter for the Interleukin-1 (IL-1R) and Toll-like receptors (TLRs). In normal healthy cells, MyD88 is thought to be held in an auto-inhibitory state with its own death and TIR domains fused together in negative self-regulation until activated by appropriate receptor mediated ligand engagement. Observation CADD derived small molecule compounds inhibit MyD88 dimer formation and protect against Staphylococcal enterotoxin B (SEB) induced death in animal models. Hypothesis Based on this observation we hypothesize that MyD88 specific small molecule inhibitors may be useful in treating DLBCLs bearing MyD88L265P. Approach Using in vitro and in vivo studies we characterize MyD88 specific SMIs for the ability to inhibit tumor cell proliferation and signaling in cancer cells bearing the oncogenic mutation MyD88L265P. Results 1) MyD88 SMIs are able to inhibit cell proliferation of DLBCLs bearing the MyD88L265P as measured by MTS cell proliferation assay, 2) recombinant MyD88 and SMIs exhibit unique binding chromatograms in comparison to DMSO controls as measured by thermal shift assay and 3) MyD88 SMIs are partially able to inhibit LPS activated TLR4 cell NF-kB signaling in comparison to the TLR4 specific inhibitor TAK242. Future studies defining the molecular mechanism of this mutation with additional human patient tumor isolates will inform and propel development of novel therapeutics to counteract both inflammation as well as tumor formation.