Researchers Develop New Molecule, 123C4, with Possibility to Treat ALS

Researchers have developed a molecule called 123C4 that targets the EphA4 receptor, which is known to contribute to the development of amyotrophic lateral sclerosis (ALS), according to a new study.

The paper, “Potent and Selective Epha4 Agonists for the Treatment of ALS,” appeared in the journal Cell Chemical Biology. Its results may pave the way for the design of novel therapies that delay disease progression in ALS and possibly other diseases.

Previous studies have identified the EphA4 receptor as a disease-modifying player whose activity is critical for the progression of motor neuron degeneration and other conditions, including spinal cord and brain injury, Alzheimer’s disease and certain cancers in the gastrointestinal tract.

Studies with ALS mice genetically altered to express low levels of the EphA4 receptor also found that these animals lived longer. Targeting the protein with drug inhibitors, for this reason, seemed promising.

“Research in assessing the therapeutic value of EphA4 for these diseases has been hampered, however, by the lack of suitable pharmacological EphA4-inhibitors,” Maurizio Pellecchia, the study’s senior author, said in a news release. “While the exact mechanism responsible for the therapeutic efficacy of our agent, 123C4, is still to be fully understood, we are confident that 123C4 — or its derivatives — will find wide application in preclinical studies as well as human clinical trials for the treatment of ALS and potentially other human disorders.”

Using a mouse model of ALS and a wide array of modern laboratory techniques, researchers tested more than 100,000 drug candidates to investigate whether they could successfully block the EphA4 receptor.

From this research, the scientists designed 123C4, a molecule that selectively binds to the EphA4 receptor in neurons. Importantly, 123C4 was shown to effectively delay ALS progression in mice.

“Prior to this current work, no bona fide EphA4 targeting agent with demonstrated efficacy in animal models of ALS had been reported,” the researchers added. “It has been a long and difficult journey to derive 123C4.”

Although the exact mechanisms by which 123C4 exerts its therapeutic action are still unknown, Pellecchia said that 123C4 is an agonist, meaning that it acts by activating the EphA4 receptor in neurons rather than by inhibiting it.

“We show that 123C4 interacting with EphA4 causes the receptor to be internalized by a process known as endocytosis — a process initiated only by an agonist,” he said. “We hypothesize that by inducing receptor internalization, 123C4 effectively removes EphA4 from the surface of motor neurons.”

Despite these promising results, 123C4 has a long way to go before it can become a viable drug candidate to treat ALS patients.

“As in any preclinical study, we must acknowledge that several obstacles are still in the way of translating agents like 123C4 into viable therapeutics,” Pellecchia said. “But Iron Horse Therapeutics, a biotech company in San Diego, is taking steps to progress this class of agents into the clinic.”

The research team is also planning to design novel molecules similar to 123C4 with either blocking or enhanced activating action to be tested in animal models of ALS.

“In collaboration with Iron Horse Therapeutics, we hope these additional studies will further facilitate the translation of these agents into novel treatments,” Pellecchia said.