Development of Novel Alkaloid Derivatives For the Treatment of Chronic Myeloid Leukemia

The majority of chronic myeloid leukemia (CML) patients can be treated with and respond to imatinib mesylate (Gleevec). Imatinib is known to inhibit BCR-ABLl kinase activity, and is effective for the treatment of the majority of CML patients. Multiple mutations have been found in patients resistant to imatinib treatment, including many located in the BCR-ABLl tyrosine kinase domain (e.g. E255K and T315I). Matrine is a bioactive alkaloid from Sophora flavescens and has been shown to inhibit several types of cancers and is used in Chinese medicine. The goal of this study is to develop new matrine derivatives that inhibit growth or induce apoptosis of imatinib-resistant CML cells. In vitro toxicity assays were performed using CML cells and various compounds, including matrine derivatives. Initial results indicate that there is approximately a 70% increase in apoptosis within 72 h of treatment in CML cells when treated with matrine, open matrine, and AMA3. After testing a second-round of derivatives, 156 and 159, it was determined that there is a significant increase in apoptosis of CML cells, especially when treated in combination with Imatinib. However, all derivatives require a concentration of at least 40 microM and induce apoptosis in NIH3T3 cells (fibroblast control cells). It appears though that 156 and 159 combination treatment with Imatinib is effective against E255K cells, but not T315I cells. Therefore, refinement of these inhibitors is warranted