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Alterations to the broad-spectrum formin inhibitor SMIFH2 improve potency

Marina Orman, Maya Landis, Aisha Oza, Deepika Nambiar, Joana Gjeci, Kristen Song, Vivian Huang, Amanda Klestzick, Carla Hachicho, Su Qing Liu, Judith M. Kamm, View ORCID ProfileFrancesca Bartolini, Jean J. Vadakkan, Christian M. Rojas, View ORCID ProfileChristina L. Vizcarra
doi: https://doi.org/10.1101/2022.03.10.483826
Marina Orman
1Department of Chemistry, Barnard College, New York, NY, USA
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Maya Landis
1Department of Chemistry, Barnard College, New York, NY, USA
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Aisha Oza
1Department of Chemistry, Barnard College, New York, NY, USA
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Deepika Nambiar
1Department of Chemistry, Barnard College, New York, NY, USA
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Joana Gjeci
1Department of Chemistry, Barnard College, New York, NY, USA
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Kristen Song
1Department of Chemistry, Barnard College, New York, NY, USA
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Vivian Huang
1Department of Chemistry, Barnard College, New York, NY, USA
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Amanda Klestzick
1Department of Chemistry, Barnard College, New York, NY, USA
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Carla Hachicho
1Department of Chemistry, Barnard College, New York, NY, USA
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Su Qing Liu
1Department of Chemistry, Barnard College, New York, NY, USA
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Judith M. Kamm
1Department of Chemistry, Barnard College, New York, NY, USA
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Francesca Bartolini
2Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY, USA
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  • ORCID record for Francesca Bartolini
Jean J. Vadakkan
1Department of Chemistry, Barnard College, New York, NY, USA
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Christian M. Rojas
1Department of Chemistry, Barnard College, New York, NY, USA
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Christina L. Vizcarra
1Department of Chemistry, Barnard College, New York, NY, USA
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  • ORCID record for Christina L. Vizcarra
  • For correspondence: cvizcarr@barnard.edu
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ABSTRACT

SMIFH2 is a small molecule inhibitor of the formin family of cytoskeletal regulators that was originally identified in a screen for suppression of actin polymerization induced by the mouse formin Diaphanous 1 (mDia1). Despite widespread use of this compound, it is unknown whether SMIFH2 inhibits all human formins. Additionally, the nature of protein/inhibitor interactions remains elusive. We assayed SMIFH2 against human formins representing six of the seven mammalian classes and found inhibitory activity against all formins tested. We synthesized a panel of SMIFH2 derivatives and found that, while many alterations disrupt SMIFH2 activity, substitution of an electron-donating methoxy group in place of the bromine along with halogenation of the furan ring increases potency by approximately five-fold. Similar to SMIFH2, the active derivatives are also pan-inhibitors for the formins tested. This result suggests that while potency can be improved, the goal of distinguishing between highly conserved FH2 domains may not be achievable using the SMIFH2 scaffold.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted March 10, 2022.
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Alterations to the broad-spectrum formin inhibitor SMIFH2 improve potency
Marina Orman, Maya Landis, Aisha Oza, Deepika Nambiar, Joana Gjeci, Kristen Song, Vivian Huang, Amanda Klestzick, Carla Hachicho, Su Qing Liu, Judith M. Kamm, Francesca Bartolini, Jean J. Vadakkan, Christian M. Rojas, Christina L. Vizcarra
bioRxiv 2022.03.10.483826; doi: https://doi.org/10.1101/2022.03.10.483826
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Alterations to the broad-spectrum formin inhibitor SMIFH2 improve potency
Marina Orman, Maya Landis, Aisha Oza, Deepika Nambiar, Joana Gjeci, Kristen Song, Vivian Huang, Amanda Klestzick, Carla Hachicho, Su Qing Liu, Judith M. Kamm, Francesca Bartolini, Jean J. Vadakkan, Christian M. Rojas, Christina L. Vizcarra
bioRxiv 2022.03.10.483826; doi: https://doi.org/10.1101/2022.03.10.483826

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