New powerful drug candidate can improve a failing heart’s function

Led jointly by researchers from the Cardiovascular Research Center and The Experimental Therapeutics Institute at Mount Sinai, the study has discovered a powerful molecule called N106, treatment with which increased heart muscle contraction to improve heart function so far in human heart cell and animal studies.

"In the near future our multidisciplinary research team hopes to launch the first clinical trials to test this promising medicine in heart failure patients," says Roger Hajjar, MD, Director of the Cardiovascular Research Center at Mount Sinai, who led the study. "This first-in-class small molecule targets a known cellular pathway, improves heart failure cell abnormalities, and may provide an essential future treatment for these patients."

Heart failure occurs when the heart becomes too weak to properly pump and circulate blood through the body. N106 may counter this by directly docking to and activating an enzyme, E1 ligase, which turns up the function of another, SERCA2a (Sarcoplasmic Reticulum Calcium ATPase). SERCA2a is a critical protein responsible for the proper flow of charged particles (e.g. calcium) in and out of heart muscle cells, with the charge flow needed to drive muscle contraction. Abnormal calcium cycling and decreased expression of SERCA2a in heart muscle cells is a major hallmark of heart failure, forcing the heart to work harder and grow larger, even as it weakens.

Interestingly, the study results suggest that the new compound may turn up the action of SERCA2a through a process called SUMOylation, where a SUMO protein (Small Ubiquitin-like Modifier) is attached to other proteins to change their function. "By activating SUMOylation of SERCA2a, this compound directly benefits the health of cardiac cells with heart failure attributes," says Dr. Hajjar.

Like most currently available drugs, the study compound, N106, is a "small molecule," with a molecular weight low enough to efficiently diffuse into cells and have its effect. Treatments that are not small molecules include those based on antibodies, which are much larger and more complex (and often more expensive) than small molecules.

"There is a critical need for novel targets and treatment strategies for heart failure. Our new discovery of the promising compound N106 is a very exciting milestone for greater precision and targeted therapies for the debilitating condition," said Bob DeVita, PhD, Director of Medicinal Chemistry at Icahn School of Medicine at Mount Sinai, whose team characterized N106 through in-depth compound screening to validate its specific SUMOylation capabilities.

"Team science and collaboration is incredibly important to identifying future powerful and promising medicines for cardiovascular diseases such as heart failure, which is growing in prevalence and now affects 26 million people globally and nearly 6 million in the United States," said Roberto Sanchez, PhD, Director of the Structure-Based Drug Discovery Core of the Experimental Therapeutics Institute at Mount Sinai, whose team computationally identified and characterized the interactions between compound N106 and its target.