New myosin inhibitors can drug the brain without stopping the heart

A decade ago, when Courtney Miller of Scripps Research in Florida found that blocking a specific protein can interrupt methamphetamine addiction in mice, it was difficult to imagine drugs targeting that protein ever coming to the clinic. But two papers published last week describe her work developing a lead candidate for treating methamphetamine use disorder and provide data to show that a related compound for treating glioblastoma is ready for clinical trials.

The target Miller homed in on is a myosin protein. Myosins are tiny motors; they clamp onto the cell’s actin skeleton and pull, generating force that cells use to move cargo, power muscle contractions, and pinch off the divisions between cells during replication. In the brain, nonmuscle myosin II (NMII) is important for forming new synapses.

While their functions are diverse, myosins are similar in structure. NMII is so much like cardiac myosin, which keeps the heart beating, that researchers believed it to be impossible to target safely. A molecule that can inhibit all myosins, blebbistatin, has a tendency to stop the hearts of mice.

Miller landed a grant in 2015 to develop new, more-selective inhibitors for NMII through a funding mechanism “specifically designed to help academic investigators bridge the gap of bringing new medications to the clinic,” she tells C&EN. She used that money to begin a medicinal chemistry campaign that found more-specific derivatives to replace an inhibitor that could never have been a safe drug (Cell 2025, DOI: 10.1016/j.cell.2025.06.006).

The team used what Miller calls a “brute force” medicinal chemistry approach that involved synthesizing about 500 blebbistatin derivatives. After putting these compounds through a battery of tests for solubility, photostability, ability to block various myosins in a test tube, and ability to interrupt cell division, the researchers found molecules that could block nonmuscle myosins without harming heart or skeletal muscles.

Miller cofounded a company, Myosin Therapeutics, in 2020 to develop the results of that screen, including a tool compound for research use and an inhibitor that she hopes to develop to treat methamphetamine use disorder.

Keunjung Heo, a postdoctoral researcher at Boston Children’s Hospital, has already used one of Myosin’s compounds to show that blocking NMII can promote healing following nerve injury in mice. She says it is encouraging that researchers can now target myosin using a compound with better solubility and specificity than blebbistatin. “However, the systemic effects of NMII inhibitors remain largely unknown,” she adds in an email. Learning more about the molecules’ effects on the rest of the body will be key for developing them in the clinic.

Alongside substance use disorder, Myosin’s pipeline also holds an NMII-targeting molecule that is being developed for glioblastoma.

For years, Mayo Clinic physician-scientist Steven Rosenfeld has been trying to convince colleagues that nonmuscle myosins are critical in glioblastoma because tumor cells are more dependent on myosin than are healthy cells. But there’s a hitch: there are two subtypes of NMII, A and B, and removing just one subtype causes cells to upregulate the other so dramatically that the cells grow better than they would without treatment.

Between that double bind and the risk of side effects from blocking heart or skeletal myosins, Rosenfeld has grown accustomed to hearing from other experts that myosin was impossible to block safely. But then a US National Institutes of Health program officer introduced him to Miller, and the two research groups teamed up to test one of the firm’s compounds, MT-125, against glioblastoma in mice (Cell 2025, DOI: 10.1016/j.cell.2025.05.019).

The researchers found that MT-125 strikes just the balance of specificity needed to treat glioblastoma and that it modestly increases the lifespan of mice with the cancer. When combined with other approved drugs, the molecule dramatically improved the animals’ survival. According to glioblastoma researcher Jerome Irianto of Florida State University, this second paper is “rich in both mechanistic insight and therapeutic promise.”

The US Food & Drug Administration recently green-lighted the firm to start testing MT-125 in first-in-human trials. Earlier this year, Myosin Therapeutics raised an additional $3 million in seed funding to support this work.

It’s gratifying to finally show some proof that myosin can be inhibited safely and confer some benefit in animal models, Rosenfeld says. “Courtney and I have been working in the wilderness for a long time.” Still, he cautions that any potential benefit to patients may be years away from being realized. “Patients who have this disease are understandably deeply concerned about finding a way to beat it, and I don’t want to raise hope unnecessarily.”