Published on Fri Jul 09 2021

Cellular toxicity of iHAP1 and DT-061 does not occur through PP2A-B56 targeting

Vit, G., Duro, J., Rajendraprasad, G., Hertz, E. P., Holland, L., Weisser, M. B., McEwan, B., Lopez-Mendez, B., Montoya, G., Mailand, N., Maeda, K., Kettenbach, A., Nilsson, J.

Small molecule compounds iHAP1 and DT-061 have recently been reported to stabilize specific PP2A-B56 complexes to mediate cell killing. We show that this is not the case and question key findings in these papers.

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Abstract

PP2A is an abundant phosphoprotein phosphatase that acts as a tumor suppressor. For this reason, compounds able to activate PP2A are attractive anticancer agents. The small molecule compounds iHAP1 and DT-061 have recently been reported by Leonard et al. (2020) and Morita et al. (2020) in Cell to selectively stabilize specific PP2A-B56 complexes to mediate cell killing. Here, we show that this is not the case and question key findings in these papers. Through genome wide CRISPR-Cas9 screens, we establish the biological pathways targeted by these compounds. We find that iHAP1 directly targets microtubule assembly both in vitro and in vivo and thus works as a microtubule poison. In contrast, DT-061 disrupts both the Golgi apparatus and the endoplasmic reticulum and we directly visualize DT-061 in cytoplasmic granules that co-localize with Golgi markers. Our work argues that iHAP1 and DT-061 cannot be used for dissecting PP2A-B56 biology.