Preclinical studies of Apogossypolone: a new nonpeptidic pan small-molecule inhibitor of Bcl-2, Bcl-XL and Mcl-1 proteins in Follicular Small Cleaved Cell Lymphoma model

Follicular Lymphoma (FL) is fifth leading diagnosed cancer estimated with over 63,000 new patients in 2007 within the United States. FL is the most common type of low grade lymphoma and the second most common subtype of lymphoma worldwide. The natural history of FL has not changed over the last 3 decades with median survival ranging from 7–10 years; the disease is considered incurable using various anti-cancer agents [1-3]. Current treatment strategies are aimed at producing remissions, preserving vital organ function and enhancing patients' quality of life [4]. Phase II trials of CHOP followed by Tositumomab/Iodine I-131 demonstrated progression free survival of 67% of patients [5]. Phase III trials of Rituximab shows improved progression free survival in relapsed/resistant FL and enhanced remission induction when used with CHOP [6], with these improvements in the treatment, to date there is not a cure except for a limited number of patients who present with localized disease. Therefore, developing targeted therapy to proteins such as Bcl-2 that prevent death of lymphoma cells is advantageous.Bcl-2 plays an important role in the lymphomagenesis of FL. Bcl-2 was originally discovered in FL as a proto-oncogene involved in the t(14;18) chromosomal translocation [7-9]. This genetic event is found in more than 85% of FL. It has been shown that transfection of Bcl-2 into B-cell lines could increase cell viability and decrease apoptosis of lymphoma cells and additionally, confers resistance of these cells to chemotherapeutic drugs [10]. Thus, interfering with Bcl-2 function is hypothesized to lead to apoptosis of lymphoma cells. Therefore, Bcl-2 is a rational therapeutic target because of its role in regulating the apoptotic pathway.Structural analysis of the binding clefts in Bcl-2 and Bcl-XL using X-ray crystallography and NMR spectroscopy showed conserved similarity in the BH1, BH2, and BH3 domains. These domains create a hydrophobic surface pocket that may represent a