Development Of A Novel Class Of Microtubule Destabilizing Agents With Selectivity Against Diffuse Large B-Cell Lymphoma (Dlbcl) With B-Cell Receptor (Bcr) Activation

To identify drugs with preferential activity against phenotypically defined subtypes of DLBCL, we carried out a high throughput screening of 100,000 drug-like compounds in two cell lines with and without tonic BCR activation. After 3 rounds of progressive viability screening we identified a small molecule, named Li5, which decreased viability of BCR-DLBCLs. In an extended DLBCL panel including cell lines with tonic or chronic (OCI-Ly1, OCI-Ly7, Farage, OCI-Ly10), and no (Toledo, Karpas422, Pfeiffer) BCR activation, we confirmed that Li5 is over 40 times more selective against DLBCL with tonic or chronic BCR activity (P= 0.001). To determine whether this differential effect is maintained in animal models, we formulated Li5 and evaluated its toxicity in C57BL/6 mice. Li5 was administered up to 200 mg/kg without evidence of toxicity in biochemical and histological assays. To asses the selective anti-lymphoma effect, we xenografted two BCR-DLBCL cell lines (OCI-Ly1 and OCI-Ly7) and a non-BCR-DLBCL cell line (Toledo) into SCID mice. Once tumors developed, we administered 10 mg/kg/day of Li5 or vehicle. Li5 significantly decreased lymphoma size in OCI-Ly7 and OCI-Ly1 mice (P < 0.005 and P= 0.005, respectively, vs. vehicle) but not in Toledo mice (P= n.s., vs. vehicle), indicating the compound holds its selectivity in vivo.