RT Journal Article
SR Electronic
T1 Alterations to the broad-spectrum formin inhibitor SMIFH2 improve potency
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.03.10.483826
DO 10.1101/2022.03.10.483826
A1 Marina Orman
A1 Maya Landis
A1 Aisha Oza
A1 Deepika Nambiar
A1 Joana Gjeci
A1 Kristen Song
A1 Vivian Huang
A1 Amanda Klestzick
A1 Carla Hachicho
A1 Su Qing Liu
A1 Judith M. Kamm
A1 Francesca Bartolini
A1 Jean J. Vadakkan
A1 Christian M. Rojas
A1 Christina L. Vizcarra
YR 2022
UL http://biorxiv.org/content/early/2022/03/10/2022.03.10.483826.abstract
AB 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 StatementThe authors have declared no competing interest.