Chemical Biology

MAP4K4 mediates human cardiac muscle cell death: Human pluripotent stem cell-derived cardiomyocytes for target validation and drug development

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  Kathryn Chapman, PhD

  Group Leader
  Domainex Ltd

Cardiac muscle cell death due to acute ischemic damage (myocardial infarction, “heart attack”) remains the single commonest cause of death and disability worldwide, with 7 million new cases per year. Heart disease is projected to increase as the population ages, and its socio-economic burden to rise for the foreseeable future. Current therapies restore blood flow (reperfusion) or decrease the heart’s workload, improving myocyte survival only through extrinsic effects. Although directly suppressing cardiomyocyte death is logical, no existing clinical counter-measures target the relevant intracellular pathways. Progress has been hampered by lack of validation in pre-clinical human models.
Professor Michael Schneider has demonstrated that Mitogen-activated Protein Kinase Kinase Kinase Kinase-4 (MAP4K4) is activated in failing human hearts and relevant rodent models. Using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM), he has demonstrated that death induced by oxidative stress requires MAP4K4. Specifically, MAP4K4 shRNA confers protection to hiPSC-CMs.
Working in collaboration with the drug discovery services company Domainex, a novel highly specific MAP4K4 small-molecule inhibitor - DMX-5804 - has been developed. Its ability to enhance cell survival, mitochondrial function, and calcium cycling in hiPSC-CMs has been demonstrated. Furthermore, DMX-5804 provides proof of principle that drug discovery guided by hiPSC-CM assays can predict efficacy in vivo, since this compound reduces the volume damaged by ischemia-reperfusion injury in mice by nearly 70%.
These experiments implicate MAP4K4 as a well-posed target for suppression of human cardiac cell death, and highlight the utility of hiPSC-CMs for drug development in common acquired cardiac disorders.