By Anette Breindl Senior Science Editor

"With the advent of targeted cancer therapies, what we've found is that many of them are cardiotoxic," Saptarsi Haldar told BioWorld Today. "Pathways that are effective in cancer are toxic in the heart."

In the May 17, 2017, issue of Science Translational Medicine, Haldar, who is an associate investigator at the Gladstone Institute of Cardiovascular Disease, and his colleagues showed that a class of epigenetic drugs, the BET bromodomain inhibitors, may be not just an exception to that rule, but a class of drugs that has therapeutic utility in heart failure.

The team showed that the bromodomain inhibitor JQ-1 had therapeutic benefits in two separate animal models of advanced heart failure, but did not affect the beneficial changes to heart muscle cells that are a consequence of exercise.

The paper shows a potential new approach to heart failure an indication that, with a five-year survival rate of 60 percent, needs them.

It also shows a potential approach to another vexing problem, namely drugging transcription factors.

"There's a surprisingly tractable therapeutic index for drugging transcription in diseases," Haldar said.

While BRD4 is not itself a transcription factor, inhibiting it "dampens the transcription factor-driven network that's driving the disease . . . This is really about dampening transcriptional rewiring," he added.

In heart failure, those happen to be innate immune signaling and fibrotic signaling. Experiments in cardiac cells derived from induced pluripotent stem cells (iPSCs) showed that JQ-1 acted by blocking the activation of innate immune and profibrotic pathways, essentially preventing heart cells from rewiring themselves in maladaptive ways in response to being chronically overworked.

Haldar said the original idea to test whether the compound would have an effect in heart failure was based on "an educated guess."

Previous work had shown that certain epigenetic marks, namely acetyl marks on lysines, play a role in heart failure.

"There is a lot known about lysine acetylation in heart failure," Haldar said, and there had been previous attempts at targeting the process, which had "fallen to the wayside, in part because of issues with therapeutic index."

Even studying the molecular details of lysine acetylation's role in heart failure was challenging, because genetic approaches are not viable.

The problem became tractable with the synthesis of JQ-1 in the laboratory of James Bradner, who is a co-author on the Science Translational Medicine paper. The compound, which has been used to gain insight into epigenetic aspects of a large number of biological processes thanks to the decision of its developers to distribute it freely, targets BRD4, a "reader" protein that recognizes acetylated lysines. (See BioWorld Insight, Aug. 12, 2013.)

With the advent of JQ-1, Haldar said, "we immediately made the connection that here's a target BRD4 that you could specifically modulate that is recognizing acetyl-lysines on chromatin."

The team initially published work in 2013 showing that JQ-1 affected cellular processes in heart failure, and was an effective therapeutic in mice when given very early in the disease.

Patients, though, don't show up in their doctor's office very early in the disease. They show up with "pre-existing, often chronic heart failure," Haldar said.

At that point, the heart has already undergone significant remodeling that includes fibrosis and an activation of innate immune pathways.

The work now published in Science Translational Medicine showed that JQ-1 had effects even when given to mice that had established heart failure either due to a heart attack, or pressure overload, but did not block exercise-induced remodeling.

The team is hoping to test JQ-1 derivatives in large animal models, and ultimately take them into the clinic. Haldar is a co-founder of Tenaya Therapeutics Inc., a company launched in December with a $50 million series A financing from The Column Group. Haldar said that while he holds a patent on BET protein inhibition in heart disease, BET proteins are only "one of many targets/pathways that Tenaya is considering."

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Researchers show cancer drug class has cardiac benefits - BioWorld Online