Boehringer, Vanderbilt University to develop cancer MCL1 inhibitors in third team-up

Boehringer Ingelheim
Boehringer Ingelheim and Vanderbilt University will work on MCL1 inhibitors in their third cancer research collaboration. (Boehringer Ingelheim)

Cancer cells are different from normal cells in that they can avoid a naturally programmed cell death process known as apoptosis and grow almost indefinitely. In their third collaboration, Boehringer Ingelheim and Vanderbilt University have their eyes on a target that helps cancer cells evade death.

The pair will focus on developing novel chemical therapeutics against the myeloid cell leukemia 1 (MCL1) protein, which scientists believe is responsible for that rogue growth and resistance to chemotherapy and is therefore a promising cancer target. The idea is to inhibit the overexpressed “pro-survival protein” (or “anti-apoptotic protein”) so programed cell death can take place in cancer cells.

“MCL1 is one of the top ten overexpressed genes in human cancer where it plays a role as a survival factor,” said Lawrence J. Marnett, Ph.D., dean of basic sciences in the Vanderbilt University School of Medicine, in a statement. The challenge is that MCL1 has been shown to interact with many other proteins, so “candidate drugs need to disrupt high affinity protein-protein interactions,” said Marnett.

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BI and the university will build the research partnership on discoveries made in the lab of Stephen Fesik, Ph.D., a cancer researcher at Vanderbilt.

RELATED: BI teams with Vanderbilt U to pursue novel cancer attack against KRAS

Fesik’s team has discovered and optimized a series of potent and selective MCL1 inhibitors that “exhibit picomolar binding affinity and mechanism-based cellular efficacy,” the team reported in a recent study published in the Journal of Medicinal Chemistry.

No approved therapies currently exist that directly target MCL1, but BI and Vanderbilt are not the only ones in the field. A team of Australian scientists previously found that MCL1 inhibitors could work in treating multiple myeloma, and they have a candidate dubbed S63845 in progress. Amgen’s AMG 176 and AstraZeneca’s AZD5991 are already in first-in-human studies on relapsed or refractory hematologic malignancies.

MCL1 marks the third joint project between BI and the Fesik lab. They are already working on drugs that directly target a cancer-causing mutation in the KRAS gene, and in their expanded partnership last year, on a novel target called SOS, which can indirectly regulate KRAS.

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