Small molecule offers big hope for heart disease sufferers

Live long enough and you will likely suffer from some form of heart disease. Blockages in arteries can restrict heart flow—a condition known as ischemia—and lead to a heart attack with damage to the heart muscle. To protect the heart against injury during heart attack, Yale researchers are studying small molecules that could be easily administered with minimal risk to patients with coronary artery disease.

This small molecule program—which aims to develop drug candidates that are safe, efficient, and easy to administer—is the outcome of a collaboration among Yale laboratories in immunology, chemistry, and cardiology, and a lab at SUNY University at Buffalo. Research on the small molecule agonists, as they are known, appeared in the journal Circulation.

A heart attack usually starts with a blood clot blocking the large coronary artery. The typical treatment is to re–establish blood flow by opening the blocked artery. The problem, said Lawrence H. Young, M.D., professor of medicine (cardiology) and of cellular and molecular physiology, is that most patients still sustain damage to the heart. “Prolonged ischemia leads to cell death,” said Young, “which in turn defines a heart attack.”

The drug candidate being developed at Yale builds on the heart’s natural protective function. When the heart loses oxygen it releases a protein called macrophage migration inhibitory factor (MIF). Secreted MIF protects the heart muscle by increasing the activity of an enzyme known as AMP‒activated protein kinase (AMPK)‒that maintains energy stores and metabolism even when the heart is starved for oxygen. The discovery of this protective action emerged four years ago from a collaboration between Young and Richard Bucala, M.D., professor of medicine, pathology, and of epidemiology and public health. The collaborators also found this cardioprotective pathway to be influenced by an MIF gene polymorphism, suggesting that therapies could be tailored to a patient’s particular genetic profile.

For about six years Bucala had also been working with William L. Jorgensen, Ph.D., Sterling Professor of Chemistry, to design small molecule antagonists to block inflammation in patients with autoimmune disorders. Bucala specializes in autoimmunity and Jorgensen is one of just a handful of Yale professors who synthesizes compounds on the path to drug discovery. The types of drugs the researchers were looking to design—ones that blocked the action of MIF and prevented inflammation—could be available for the first time in pill form.

What they found about its role in protecting the heart led them to reverse course—instead of blocking MIF, they looked for a way to enhance MIF as a treatment for heart attacks.

Jorgensen had developed a software called BOMB (biochemical and organic model builder), to design such inhibitors as anti–HIV agents. He used BOMB to create 3–D computer models of thousands of molecules that would fit well into the binding site of MIF. He selected molecules, which were synthesized by co-workers in his laboratory, and subsequently sent to Bucala’s lab for testing. Some of the molecules, they found, were inhibitors, as expected. Surprisingly, a few were agonists.

Knowing that MIF served a protective function in the heart, Bucala, Jorgensen and Young honed in on this discovery. In looking for a way to inhibit MIF, they had stumbled across a way to activate it, and opened a new possibility for heart–protective drugs.

Jorgensen said it’s the first time in his career he’s experienced such serendipity. “I’m normally synthesizing inhibitors,” he said. “I don’t know how to design an agonist. It would have been ignored if Drs. Bucala and Young hadn’t made the discovery that if you up–regulate MIF action it can be beneficial to the heart.”

These small molecules were the first to be discovered that could augment the action of the MIF receptor. Working with Young and one of Young’s former trainees Ji Li, Ph.D., now at the University at Buffalo (SUNY), the team found that MIF agonists, mimicking the heart’s own protective action, limited ischemic damage in the heart. It was a first–of–its–kind discovery.

The most potent of the agonists they found was called “MIF20,” which was shown in mouse hearts to enhance the activation of AMPK and cellular glucose uptake. When mouse hearts were treated with MIF20 prior to the cessation of blood flow during ischemia, akin to what patients undergo during a heart attack, it significantly prevented injury and improved later heart contractile function.

The research must be replicated in larger animal models as well as other preclinical experiments to assess the molecule’s safety before human drug trials can begin. “We’ve gone from the discovery of a novel molecular mechanism to early stage animal studies,” Young said. “There will be a year or two before early clinical studies can begin.”

Patents filed by Yale’s Office of Cooperative Research (OCR) cover these first–in–class small molecule agonists. Bucala said OCR was instrumental in bringing the Yale investigative groups together. “They promote research translation,” Bucala said of OCR, which works with faculty to protect intellectual property coming from their discoveries, identifies partners, helps find opportunities for corporate sponsorship of research, and ultimately facilitates the maturation of basic science concepts into real–world solutions. “In research, we’re usually all about understanding disease, but we rarely have an opportunity to talk to one another to find ways to actually devise new therapies.”

Collaborations on small molecule agonists are already moving forward in other therapeutic areas. Bucala said he is working on research with Yale’s neurosurgery department using small molecule agonists to treat traumatic brain injury and other conditions where MIF’s activity could be beneficial to patients.