Abstract 2130: Small molecule activation of diaphanous-related formins as a novel anti-cancer strategy.

Abstract

Abstract Formin-based cytoskeletal remodeling contributes to structural rearrangements that support an array of cellular demands, including chemotaxis and cell division. The Diaphanous formin family is managed in cells by Rho small GTP-binding proteins. Rho-GTP binding to the formin interferes with the intramolecular interaction between the Dia-inhibitory and -autoregulatory (DID & DAD) domains that flank the critical formin homology-2 (FH2) domain. The FH2 domain can then interact with microtubules to stabilize microtubule dynamics and loosely associate with barbed ends of polymeric actin filaments to add actin monomers. As a consequence of monomer consumption into filaments, formins also activate the MAL/MRTF-SRF transcription factor axis. DAD-derived peptides can activate formins in cells by interrupting the DID-DAD autoregulatory mechanism. We screened for drug-like small molecules with in vitro, cellular, and in vivo activities that could mimic the impact of DAD peptides. Two chemically similar molecules, called the Intramimics (IMMs) were identified. Both molecules (IMM-01 and -02) blocked DID-DAD binding in vitro, induced actin/microtubule stabilization in cells, activated SRF, and impaired cell-cycle progression. The IMMs each reduced xenograft tumor growth in mice. Due to their novel activity on formins, the IMMs represent an innovative therapeutic strategy for the study and treatment of diseases impacted by defects in cell structure, including autism, neurodegenerative disease, and cancer. Citation Format: Leanne L. Lash, Arthur S. Alberts. Small molecule activation of diaphanous-related formins as a novel anti-cancer strategy. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2130. doi:10.1158/1538-7445.AM2013-2130