A phenotypic screen identified KEAP1-kelch domain blockade as a mechanism to restore cardiac function in the setting of chronic severe hemodynamic stress

Upson, J. J.; Schnackenberg, C. G.; Lawhorn, B. G.; Chen, Q.; Sweet, D. T.; Chendrimada, T. P.; Brooks, C. A.; Burgert, M. E.; Louer, C. T.; Zacco, A. E.; Moench, I. A.; Basilla, J. B.; Boyer, J. G.; Ivashchenko, C. Y.; Manns, S.; Bernard, R. E.; Pipes, G. C.; Eisennagel, S. H.; Bao, W.; Davenport, E.; Kuziw, J. C.; Krawiec, J. A.; Hauk, K.; Agrapides, S.; Rambo, M.; Olzinski, A. R.; Rivera, K.; Grygielko, E. T.; Jolivette, L. J.; Lepore, J. J.; Willette, R. N.; Toomey, J. R.

doi:10.1101/2025.09.24.678104

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bioRxiv · 10.1101/2025.09.24.678104

A phenotypic screen identified KEAP1-kelch domain blockade as a mechanism to restore cardiac function in the setting of chronic severe hemodynamic stress

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Abstract

A bespoke gene expression (GE) based small molecule screen in human induced pluripotent stem cell derived cardiomyocytes (iPSC-CM) was conducted with the aim of identifying drug targets and pathways with the potential to reverse heart failure (HF) pathologic GE and the resultant decompensated HF phenotype. The screen utilized a composite human-murine HF gene expression signature, a target annotated compound set, and a HF gene expression reversal scoring algorithm to identify small molecules and their associated targets as potential modulators of HF pathologic GE. Following hit triage, a lead optimization program, and compound characterization in preclinical rodent models of HF and human iPSC-CM contractility assays, KEAP1 kelch domain blockers were identified as potent efficacious agents in the restoration of contractile function in the setting of oxidant stress and pressure overload induced cardiac dysfunction.

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Upson, J. J., Schnackenberg, C. G., Lawhorn, B. G., Chen, Q., Sweet, D. T., Chendrimada, T. P., Brooks, C. A., Burgert, M. E., Louer, C. T., Zacco, A. E., Moench, I. A., Basilla, J. B., Boyer, J. G., Ivashchenko, C. Y., Manns, S., Bernard, R. E., Pipes, G. C., Eisennagel, S. H., Bao, W., Davenport, E., Kuziw, J. C., Krawiec, J. A., Hauk, K., Agrapides, S., Rambo, M., Olzinski, A. R., Rivera, K., Grygielko, E. T., Jolivette, L. J., Lepore, J. J., Willette, R. N., Toomey, J. R.. 2025-09-26. A phenotypic screen identified KEAP1-kelch domain blockade as a mechanism to restore cardiac function in the setting of chronic severe hemodynamic stress. https://doi.org/10.1101/2025.09.24.678104

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