Indirubin derivatives and uses thereof in treating chronic myelogenous leukemia
Indirubin is the major active anti-tumor component of a traditional Chinese herbal medicine used for treatment of chronic myelogenous leukemia (CML). One aspect of the invention relates to a method of treating CML using at least one indirubin derivative compound or a pharmaceutical composition thereof. Indirubin derivatives (IRDs) potently inhibited Signal Transducer and Activator of Transcription 5 (Stat5) protein in CML cells. Compound IRD 810 inhibits Bcr-Abl/Stat5 or Src/Stat5 signaling in human KCL-22 CML and imatinib-resistant human KCL-22 CML cells expressing the T315I mutant Bcr-Abl. Previous studies indicate that SFKs cooperate with Bcr-Abl to activate downstream Stat5 signaling. Activation of Stat5 was strongly blocked by IRD 810 in CML cells. IRDs disclosed herein have been identified as potent inhibitors of Bcr-Abl/Stat5 or SFK/Stat5 signaling pathway. IRDs disclosed herein are new therapeutics for wild type or T315I mutant Bcr-Abl-positive CML patients, and may also treat other solid tumors, including prostate cancer and lymphoma.
1. An IRD selected from the group consisting of IRDs 681, 682, and 684, and the pharmaceutically acceptable derivatives, solvates, salts and stereoisomers thereof, including mixtures thereof in all ratios:
2. A pharmaceutical composition comprising a therapeutically effective amount of at least one IRD according to claim 1 .
3. The pharmaceutical composition according to claim 2 , further comprising a pharmaceutically acceptable carrier.