Targeting MCL-1, cancer’s Achilles heel

A research collaboration between WEHI and the international pharmaceutical company Servier has facilitated the development of new agents targeting MCL-1, a pro-survival protein that is essential for the sustained growth of diverse cancers, particularly blood cancers

Since the 1980s, WEHI researchers have investigated the proteins that govern cells’ decisions to live or die, making many landmark discoveries about the roles of these proteins in the development and progression of cancer and other diseases. The BCL-2 family of proteins includes critical molecular regulators of apoptotic cell death, including the anti-apoptotic proteins BCL-2 and MCL-1.

Using state-of-the-art gene-targeting technologies, WEHI researchers revealed that MCL-1 is critical for the survival of a certain blood cancers. This discovery established MCL-1 as a valuable potential target for anti-cancer therapies. Indeed, MCL-1 is estimated to be essential for the sustained growth of up to a quarter of all cancers.

In 2013, WEHI established a research collaboration with the European pharmaceutical company Servier, to facilitate the development of new ‘BH3-mimetic’ agents targeting MCL-1, which were jointly discovered by Servier and Vernalis (R&D), a UK-based pharmaceutical company. The collaborationwith WEHI aimed to characterise these novel anti-MCL-1 drug candidates and help their development in various indications, with the ultimate goal of developing new therapies for cancer patients.

The collaborative team – including scientists from WEHI, The Alfred Hospital and Servier – announced in 2016 that the MCL-1 inhibitor compound, S63845, was effective in several MCL-1-dependent preclinical cancer models, and could be delivered at doses that were well tolerated by normal cells. This was the first clear preclinical evidence that inhibiting MCL1 was effective in targeting several cancer types. These discoveries underpinned phase 1 clinical trials of optimised MCL-1 inhibitors at The Alfred Hospital and The Royal Melbourne Hospital. Since then, WEHI’s research has also provided scientific rationale on the use these inhibitors in indications such as acute myeloid leukemia and breast cancer.

WEHI’s Head of Biotechnology and Commercialisation, Dr Anne-Laure Puaux said the collaboration with Servier illustrates WEHI’s availability to collaborate at many stages of drug discovery.

“In this case of S63845, our collaboration with Servier was a pre-clinical stage partnership, and proved instrumental in providing the foundation for taking this class of inhibitors to clinic for the first time. WEHI’s expertise in cell death research and understanding in the biology of MCL-1 added value to Servier’s drug discovery program,” she said.

“WEHI also has a track record of success in partnerships formed early in the drug discovery pipeline, such as in the development of potential immunotherapies as well as other anti-cancer drugs.

“Our Business Development team are open to discussing potential collaborations at a range of points spanning the drug discovery and development pipeline,” Dr Puaux said.