Image by Ed Uthman
A new compound has shown promise for treating hematologic malignancies and other cancers, according to preclinical research published in Nature.
The compound, known as S63845, targets the BCL2 family protein MCL1.
Investigators said their research on S63845 provides the first clear evidence that inhibiting MCL1 is effective in targeting several cancer types, including leukemia, lymphoma, and multiple myeloma (MM).
“MCL1 is important for many cancers because it is a pro-survival protein that allows the cancerous cells to evade the process of programmed cell death that normally removes cancer cells from the body,” said study author Guillaume Lessene, PhD, of the Walter and Eliza Hall Institute in Melbourne, Australia.
“Extensive studies performed in a variety of cancer models have shown that S63845 potently targets cancer cells dependent on MCL1 for their survival.”
About S63845
Dr Lessene and his colleagues said S63845 binds with high affinity to the BH3-binding groove of MCL1. And the compound kills MCL1-dependent cancer cells by activating the BAX/BAK-dependent mitochondrial apoptotic pathway.
In solid tumors, S63845 often wasn’t effective enough on its own. However, when the compound was combined with various kinase inhibitors, it induced a “potent cytotoxic response” in breast cancer, lung cancer, and melanoma cells.
In hematologic malignancies, S63845 proved effective when given alone.
Myeloma
The investigators said 17 of 25 MM cell lines tested were highly sensitive to S63845 (IC50 < 0.1 μ M), 6 cell lines were moderately sensitive (0.1 μ M < IC50 < 1 μ M), and 2 cell lines were insensitive (IC50 > 1 μ M).
The team also administered S63845 (at 25 mg/kg) to mice with MM. Seven of 8 mice had complete regression at 100 days after treatment.
Lymphoma
The investigators tested S63845 in 11 cell lines representative of human lymphomas. Five were highly sensitive to the compound (IC50 < 0.1 μ M), 3 were moderately sensitive (0.1 μ M < IC50 < 1 μ M), and 3 were insensitive (IC50 > 1 μ M).
The team also tested S63845 in 7 c-MYC-driven human Burkitt lymphoma cell lines and found the compound exhibited “potent cytotoxic activity” in all of them.
The investigators then tested S63845 in a c-MYC-driven mouse lymphoma model. They noted that both tumor cells and normal tissues express mouse MCL1 protein in this model.
Treatment with S63845 (25 mg/kg) for 5 consecutive days cured 70% of these mice, and the investigators said there were no evident side effects in normal tissues.
Leukemia
The investigators tested S63845 in 5 chronic myeloid leukemia cell lines, and none of them were sensitive to the compound.
However, the team also tested S63845 in 8 acute myeloid leukemia (AML) cell lines, and all of them were sensitive to the compound (IC50 4–233 nM).
When S63845 was given to mice with AML (25 mg/kg), 6 of the 8 mice achieved complete remission after 80 days.
The investigators also tested S63845 in 25 freshly derived samples from patients with AML. The team said these samples displayed a wide range of responses to S63845.
The most sensitive samples required 100- to 1000-fold less drug (to induce apoptosis) than the resistant samples or normal CD34+ progenitor cells.
Development/funding
S63845 was discovered through a collaboration between 2 pharmaceutical companies—Servier, which is headquartered in France, and Vernalis (R&D), which is based in the UK.
“[C]linical development of a MCL1 inhibitor should be launched in the near future,” said Olivier Geneste, director of oncology research at Servier.
The current research was supported through a collaboration with Servier and through funding from the National Health and Medical Research Council of Australia, the Leukemia and Lymphoma Society, Cancer Council Victoria, the Kay Kendall Leukemia Fund, Victorian Cancer Agency, Australian Cancer Research Foundation, the Victorian Government Operational Infrastructure Scheme, and the estate of Anthony Redstone.
