Abstract
Non-Hodgkin’s lymphoma (NHL) tumors include a group of heterogeneous diseases with varying natural histories and responsiveness to therapy; nonetheless, overexpression of Bcl-2 protein is seen in more than 80% of NHL. Throughout the years our laboratory succeeded in establishing a panel of B-cell lines representing various maturational stages of NHL. In this study, we have utilized a structure-based strategy to design a new class of potent nonpeptidic small-molecule inhibitor (SMI) of Bcl-2 family. TW-37, a lead compound that was designed to target the BH3 binding groove of antiapopototic Bcl-2 proteins. It binds to Bcl-2, Bcl-XL and Mcl-1 with Ki values of 290 nM, 1110 nM and 260 nM, respectively. TW-37 showed significant antiproliferative effect against Pre-B-Acute Lymphoblastic Leukemia (WSU-pre-B-ALL), Diffuse Large Cell Lymphoma (WSU-DLCL2), Follicular Small Cleaved Cell Lymphoma (WSU-FSCCL), Waldenstrom’s Macroglobulinemia (WSU-WM) and primary cells obtained from lymphoma patients, despite variations in their anti- and pro-apoptotic Bcl-2 proteins (Bcl-2, Bcl-XL, Mcl-1, Bax, Bak, Bim, Bad, BUMA and Bok). The IC50 for TW-37 varied from 165 nM in the WSU-FSCCL to 300 nM in WSU-DLCL2 cells. Apoptosis was independent of proliferative status or pathological classification of B-cell tumor. TW-37 was able to block Bim-Bcl-XL and Bim-Mcl-1 eterodimerization and induces apoptosis via activation of caspases -9, -3, PARP and DNA fragmentation. Although cell lines and patient samples expressed multiple Bcl-2 family proteins at various levels, TW-37 induced apoptosis was only strongly associated with Bax:Mcl-1 ratio. TW-37 administered to tumor-bearing SCID mice led to significant tumor growth inhibition (T/C), tumor growth delay (T-C) and Log10kill, when used at its maximum tolerated dose (40 mg/kg x 3days) via tail vein. failed to induce changes in the Bcl-2 proteins levels suggests that assessment of baseline Bcl-2 family proteins can be used to prognosticate the response to drug. These findings indicate activity of TW-37 across the spectrum of human B-cell tumors and support the concept of targeting the Bcl-2 system as a therapeutic strategy in the treatment of B-cell lymphoma.
Absorption, Distribution, and Binding Profile of ME-401, a Potent and Selective Oral Small-Molecule Inhibitor of Phosphatidylinositol 3-Kinase δ (PI3Kδ) in Animal and B-Cell Lymphoma Models
