Identification of Bisindolylmaleimide IX as a potential agent to treat drug-resistant BCR-ABL positive leukemia

Chronic myeloid leukemia (CML) therapy using BCR-ABL inhibitors is frequently challenged by the emergence of drug resistance. In a search for novel chemotherapeutic agents with genotoxic properties, we identified Bisindolylmaleimide IX, a derivative of the bisindolylmaleimide family, as a promising small-molecule compound with activity against both standard and drug-resistant forms of CML.

Our findings demonstrate that Bisindolylmaleimide IX functions as a DNA topoisomerase inhibitor, inducing DNA strand breaks and activating the Atm-p53 and Atm-Chk2 signaling pathways. These molecular events lead to cell cycle arrest and apoptosis. Notably, Bisindolylmaleimide IX exhibits a pronounced cytotoxic effect in BCR-ABL–positive cells, which display heightened DNA damage and enhanced cell cycle arrest in response to treatment. This increased sensitivity is partly attributable to reduced expression of topoisomerases in BCR-ABL–expressing cells.

Moreover, cells harboring the drug-resistant T315I BCR-ABL mutation also show increased susceptibility to Bisindolylmaleimide IX, as the compound effectively inhibits B-Raf and disrupts the downstream oncogenic signaling pathways that mediate oncogene addiction in BCR-ABL–driven leukemia.

In vivo studies using mouse models of leukemia induced by either wild-type BCR-ABL or the T315I mutant revealed that treatment with Bisindolylmaleimide IX significantly suppressed disease progression and extended survival, with minimal observed toxicity.

In summary, Bisindolylmaleimide IX represents a promising therapeutic candidate for the treatment of drug-resistant CML by simultaneously triggering BCR-ABL–dependent genotoxic stress responses and blocking critical oncogenic signaling pathways driven by BCR-ABL.