Small molecule drug triggers rapid cell death in cancer models

A team of researchers at the Broad Institute of MIT and Harvard, in a long-term project involving industry partners from Bayer and Trueline Therapeutics, have developed a compound called BRD-810 that shows promise as a therapeutic candidate for cancer. This small molecule reactivates the apoptosis cascade in tumor cells and spares healthy cells in animal models.

Apoptosis or programmed cell death is a natural final process for all cells. But many types of cancer have mechanisms that block this cascade, allowing dangerous proliferation. BRD-810 restores the normal apoptotic process by inhibiting a protein called MCL1, which normally protects cells from apoptosis. MCL1 is one of the most highly overexpressed proteins in many cancers, particularly those resistant to standard chemotherapy – making it an attractive drug target.

In a study published in Natural cancerThe team showed that their compound binds to MCL1, abolishing its protective effects and triggering cell death in cancer. Importantly, unlike other MCL1 inhibitors that have raised concerns about cardiovascular side effects in early clinical trials, BRD-810 acts quickly in cancer cells and is cleared from the body within hours in animal models. This rapid clearance minimizes the drug's potential effects on healthy cells.

“BRD-810 is a potent inhibitor with exciting potential as an anticancer agent,” said senior author Todd Golub, director of the Broad Institute. “Our team, together with our collaborators, has worked hard to optimize this compound, which has resulted in promising preclinical data, and we are committed to advancing it further.”

Ulrike Rauh, former CEO/CSO of Trueline Therapeutics and current chief development officer at Prosion Therapeutics, is the lead author of the paper.

Reactivate apoptosis

The journey to BRD-810 began more than a decade ago when Broad researchers, including members of the Broad Center for the Development of Therapeutics, began studying MCL1 inhibitors in screening tests. The first starting material they identified was too large to be a useful drug. Therefore, the team worked with collaborators at Bayer AG to analyze and refine its structure while preserving its ability to bind to MCL1. The result was the compound called BRD-810.

To evaluate the effectiveness of BRD-810, researchers used Broad's PRISM platform to examine more than 700 cell lines representing 32 different cancer lines. The compound inhibited the growth of a wide range of cancer models, including breast cancer, lung cancer, melanoma, sarcoma, lymphoma and leukemia.

Previous clinical and laboratory studies of other MCL1 inhibitors have shown that these molecules can damage heart cells, likely due to prolonged exposure to the compounds. Therefore, the team focused on optimizing the pharmacokinetic profile of BRD-810 to preserve its ability to kill tumor cells without negatively affecting cardiac cells.

In cellular models, BRD-810 effectively killed cancer cells within four hours of administration and had no effect on cardiomyocytes derived from human induced pluripotent stem cells during the same period. Working with Trueline Therapeutics, the team refined this dosing strategy in animal models to maximize anticancer activity while minimizing risks.

In mouse models, the compound triggered strong tumor regression and did not cause weight loss (used as a marker of physiological stress). Trueline Therapeutics also tested the compound in a dog model and found no signs of cardiac toxicity.

In the future, the Broad team hopes to advance BRD-810 into clinical trials as a potential treatment for a range of cancers, either as a standalone therapy or in combination with other cancer drugs to improve their effectiveness.

“I am excited about the potential of this compound,” said Rauh, who first joined the project while working as a scientist at Bayer. “It was incredibly rewarding to develop BRD-810 and witness its potential to address the challenges associated with MCL1 inhibition.

“And this project beautifully illustrates the power of combining Broad’s biological expertise and creative approaches to drug discovery with industry expertise and capabilities.”