sar405838 and Leukemia

We previously reported the design of spirooxindoles with two identical substituents at the carbon-2 of the pyrrolidine core as potent MDM2 inhibitors. In this paper we describe an extensive structure-activity relationship study of this class of MDM2 inhibitors, which led to the discovery of 60 (AA-115/APG-115). Compound 60 has a very high affinity to MDM2 (K

Topics: Animals; Antineoplastic Agents; Bone and Bones; Bone Neoplasms; Bridged Bicyclo Compounds; Cell Line, Tumor; Drug Discovery; Halogenation; Humans; Indoles; Leukemia; Mice; Molecular Docking Simulation; Neoplasms; Osteosarcoma; Proto-Oncogene Proteins c-mdm2; Pyrrolidines; Rats; Structure-Activity Relationship

Two clinical-stage anticancer drugs, the Bcl-2 inhibitor ABT-263, and the MDM2 inhibitor SAR405838 achieve complete tumor regression in animal models of leukemia but also induce acquired resistance. Elucidation of acquired resistance mechanisms and development of strategies to overcome the resistance are critical for their successful clinical development.. We employed RS4;11 and MV4;11 cell lines, two acute leukemia models, to investigate acquired resistance mechanisms for both drugs in vitro and in vivo and evaluated several treatment regimens in xenograft mouse models to improve long-term, complete tumor regression.. Resistance to either SAR405838 or ABT-263 (or its analogue ABT-737) develops in acute leukemia models in vitro and in vivo. RS4;11 and MV4;11 tumors treated with SAR405838 acquire resistance to the drug by mutation of the TP53 gene or compromise of p53 protein function. RS4;11 tumors treated with either ABT-263 or ABT-737 acquire resistance primarily through downregulation of BAX but not BAK. When acute leukemia cells become highly resistant to the MDM2 inhibitor, they retain their sensitivity to the Bcl-2 inhibitors, or vice versa. Certain sequential or combination treatment of SAR405838 and ABT-263 can achieve longer-term tumor regression than treatment with either agent alone.. Our study provides new insights into the mechanisms of acquired resistance of Bcl-2 and MDM2 inhibitors in acute leukemia models and suggests that certain sequential or combination treatment of these two distinct classes of apoptosis-inducing agents should be tested as new treatment strategies for acute leukemia in the clinic.

Topics: Animals; Apoptosis; Biphenyl Compounds; Cell Line, Tumor; Drug Resistance, Neoplasm; Humans; Indoles; Leukemia; Mice; Nitrophenols; Piperazines; Proto-Oncogene Proteins c-bcl-2; Proto-Oncogene Proteins c-mdm2; Spiro Compounds; Sulfonamides; Xenograft Model Antitumor Assays