A novel small molecule designed and synthesised by Indian researchers has shown promise in targeted killing of cancer cells. The molecule (Disarib) binds to a protein BCL2 and inhibits the protein from suppressing cell death in cancer cells. While BCL2 protein is produced in excess in cancer cells, its expression is almost undetectable in normal cells. Hence, Disarib targets and kills only cancer cells while sparing normal cells.

Inside a cell there is always a balance between proteins that promote cell death (apoptosis) and those that suppress cell death. Since the proteins (BAX and BAK) that promote cell death get bound to BCL2, normal cell death is suppressed and cancer cells are able to live longer.

A team led by Prof. Sathees C. Raghavan at the Department of Biochemistry, Indian Institute of Science (IISc), Bengaluru demonstrated that Disarib was able to disrupt the interaction of BCL2 and apoptosis-causing BAK protein and cause the death of cancer cells.

However, expression of BCL2 is low in certain cancer cell lines such as breast cancer, chronic myelogenous leukemia and cervical cancer. So the Disarib molecule will be ineffective in these cancers.

The efficiency of Disarib to cause cell death and tumour regression was far superior compared with the FDA-approved ABT199.Disarib is the culmination of eight years of collaborative research involving 24 researchers from eight different research groups across various labs.

Superior than FDA-approved molecule

Unlike the FDA-approved BCL2 inhibitor ABT199, the small molecule binds predominantly to a different domain (BH1) of BCL2 and showed better efficiency in killing cancer cells. Also, compared with ABT199 inhibitor, the small molecule synthesised by Prof. Raghavan’s team did not cause any side effects. The results were published in the journal Biochemical Pharmacology.

Earlier studies had shown that once Disarib binds to BCL2, the proteins that promote cell death were able to create holes in the mitochondria leading to death of cancer cells.

“We have experimentally tested Disarib in all possible systems and the efficiency of Disarib in selectively killing cancer cells was high,” says Supriya V. Vartak from the Department of Biochemistry, Indian Institute of Science (IISc) and one of the first authors of the study. Studies were carried out on three animal models for three different cancers — lymphoma, breast adenocarcinoma and ovarian cancer. Similarly, studies were carried out using cancer cells lines.

“In every case, both in animal studies and cancer cell lines, the efficiency of Disarib to cause cell death and tumour regression was far superior compared with ABT199 when same dosage of Disarib and ABT199 was used,” says Prof. Raghavan. “This is why the molecule has to be taken up for further investigation.”

The team has carried out quite a lot of toxicity studies already. Next step will be to test the toxicity and efficacy of the molecule in cancer cells taken from patients, and also test it in combination with known cancer drugs. If results from humanised mouse models are also encouraging then the molecule can be taken up for clinical trials in humans.

Published in The Hindu on May 5, 2017