A team of researchers at the Broad Institute of MIT and Harvard, in collaboration with industry partners at Bayer and Trueline Therapeutics, has developed a promising therapeutic candidate for cancer called BRD-810. This small molecule effectively reactivates the apoptosis cascade in tumor cells while sparing healthy cells in animal models. The research, published in Nature Cancer, highlights BRD-810's potential to overcome resistance to standard chemotherapies by targeting MCL1, a protein highly overexpressed in many cancer types.
Reactivating Apoptosis Through MCL1 Inhibition
Apoptosis, or programmed cell death, is a crucial natural process that is often blocked in cancer cells, allowing them to proliferate uncontrollably. BRD-810 restores this normal apoptotic process by selectively inhibiting MCL1, a protein that protects cells from apoptosis. MCL1 overexpression is particularly prevalent in cancers resistant to standard chemotherapies, making it an attractive drug target.
The study demonstrates that BRD-810 binds to MCL1, effectively removing its protective effects and triggering cell death in cancer cells. A key advantage of BRD-810 over other MCL1 inhibitors is its rapid action within cancer cells and its quick elimination from the body in animal models, typically within a few hours. This rapid clearance minimizes the potential for cardiovascular side effects, a concern associated with other MCL1 inhibitors in early-stage clinical trials.
Preclinical Efficacy and Safety
The development of BRD-810 began over a decade ago with initial screening tests at the Broad Institute. Researchers collaborated with Bayer AG to refine the structure of an initial lead compound, resulting in BRD-810. To assess its effectiveness, the researchers used the PRISM platform to screen more than 700 cell lines representing 32 different cancer lineages. The compound demonstrated significant growth inhibition across a broad range of cancer models, including breast cancer, lung cancer, melanoma, sarcoma, lymphoma, and leukemia.
Recognizing the potential for cardiovascular toxicity observed with other MCL1 inhibitors, the team focused on optimizing the pharmacokinetic profile of BRD-810. In cell models, BRD-810 effectively killed cancer cells within four hours of administration and did not negatively impact cardiomyocytes derived from human induced pluripotent stem cells during the same timeframe. Further refinement of the dosing strategy in animal models, in collaboration with Trueline Therapeutics, maximized anti-cancer activity while minimizing risks.
In mouse models, BRD-810 triggered strong tumor regression without causing any weight loss, a key indicator of physiological stress. Trueline Therapeutics also tested the compound in a canine model and found no markers of cardiac toxicity. These promising preclinical results pave the way for potential clinical testing of BRD-810 as a treatment for various cancer types, either as a standalone therapy or in combination with other cancer drugs to enhance their efficacy.
According to senior author Todd Golub, director of the Broad Institute, BRD-810 is a potent inhibitor with exciting potential as an anticancer agent. Ulrike Rauh, former CEO/CSO of Trueline Therapeutics and current Chief Development Officer at Prosion Therapeutics, who is the lead author of the paper, expressed her enthusiasm for the potential of BRD-810 to overcome the challenges associated with MCL1 inhibition.
