CCI-006 is a novel inhibitor of MLL-rearranged and CALM-AF10 translocated leukemias, inhibiting mitochondrial respiration and inducing mitochondrial membrane depolarization and apoptosis in a subset (7/11, 64%) of MLL-rearranged leukemia cell lines within a few hours of treatment.
Rearrangement of the mixed lineage leukemia (MLL, KMT2A) gene occurs in 5–10% of acute leukemias and is especially prevalent in infant acute leukemias (up to 70% of cases). The MLL-rearranged (MLL-r) leukemia subtype is characterized by its aggressive nature, resistance to therapy and typical occurrence of early relapse. CCI-006 is a novel inhibitor of MLL-r and CALM-AF10 translocated leukemias that share common leukemogenic pathways. CCI-006 (10 μM; 72 h) demonstrated a selective cytotoxic effect against 3 out of 4 tested MLL-r leukemia cell lines, without significantly affecting the viability of MLL-wt leukemia (n = 6) and solid tumor (n = 4) cell lines, or noncancerous cells (n = 3). CCI-006 reduced the viability of 7 out of 11 (64%) “sensitive” MLL-r leukemia cell lines to below 85% of that of vehicle-treated cells at a 10 µM dose, including cell lines derived from infant (younger than 1 year) or pediatric leukemia patients with chemo-resistant disease. CCI-006 significantly increased the percentage of cells expressing cell surface Annexin V (marker of apoptosis) in sensitive MLL-r leukemia cells within a few hours of treatment. In addition, in a JC-1 assay for mitochondrial membrane depolarization, CCI-006 induced mitochondrial depolarization in a dose-dependent manner within 1 h of treatment[1].
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