Mantle cell lymphoma (MCL) is an aggressive and incurable B cell malignancy accounting for 5% of non-Hodgkin's lymphomas. Current treatment for MCL includes multi-agent chemotherapy such as CHOP or Hyper-CVAD4 with stem cell transplantation in selected patients, but prognosis for most patients remains poor, with median survival around 2-4 years. The exact mechanism of lymphoma genesis in MCL is not known, but it is believed that MCL arises from na�ve B cells in the mantle zone of lymph node follicles and is characterized by the chromosomal translocation t(11,14) leading to over-expression of CCND1. However, murine models over-expressing CCND1 in the absence of other oncogenes including MYC do not develop lymphoma, implying that additional mechanisms may be involved in lymphoma genesis in MCL. Based on the literature, in the context of an ongoing chemical biology project, we focused on the Transforming Growth Factor-beta (TGF-beta) pathway, considering a possible biological mechanism involving cross-talk between TGF-beta and Notch1 signaling pathways for genesis of MCL. Based on our previous work implicating stilbene derivatives in modulating TGF-beta signaling, we synthesized boron-containing stilbene derivatives and tested their biological activity as potential therapeutic agents for MCL. From preliminary screening in cell-based assays using HBL-2 and Jeko-1 cell lines, we found that compound 1g specifically inhibits cell growth (IC50 6.4 �M). We are in the process of further derivatizing our lead hit compound 1g to analyze the mechanism of action including apoptosis assays and changes in expression of Notch signaling components and downstream Notch1 regulated genes. These pinacolylboronate-substituted alkene derivatives may be developed as potential therapeutic agents for MCL.

Synthesis and biological study of boron-containing alkene derivatives as potential therapeutics for the treatment of mantle cell lymphoma(MCL)

246th National Meeting (2013)

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