Abstract
Abstract Rho small GTP-binding proteins locally manage Diaphanous-related formins as they construct the cytoskeletal infrastructure that supports essential changes in cell morphology. Rho binding unlatches formin intramolecular autoinhibition. The autoinhibition is mediated by the Dia-inhibitory and -autoregulatory domains (DID & DAD) which flank the formin homology-2 (FH2) domain. The free FH2 domain guides the assembly of the linear actin and microtubule structures required for adhesion, migration, division, and polarity establishment. Microtubule stabilization is already known to be an effective anti-cancer strategy. Combined with the knowledge that formins can act as haploinsufficient tumor suppressor genes, a screen was conducted for agents that could impair autoinhibition in order to activate formins for therapeutic benefit. We have focused on two of the primary “hits” for development. VARI01 and VARI02 are nearly identical thioamide inhibitors of DID-DAD binding (IC50 values ≤ 140 nM). Exposure of cultured tumor cells to either compound triggered the expected changes in cell structure and signaling that were consistent with formin activation. These included microtubule stabilization, F-actin assembly, the activation of the transcription factor SRF, cell-cycle arrest, and eventual apoptosis. SRF senses changes in actin dynamics to activate the expression of genes that reinforce cell structure and monitor genome integrity. VARI01 and VARI02 both exhibit anti-tumor activity in xenograft studies. Ongoing studies are aimed at identifying VARI01/VARI02-sensitive tumor types and to define other potential therapeutic applications. Significance: Microtubule stabilization by taxol has proven to be an effective anti-cancer strategy, but it has significant deleterious side effects. Small-molecule formin activation serve as a novel class of anti-cancer agents that may provide tools for unlocking the biological roles of formins in signalling and disease. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4764. doi:1538-7445.AM2012-4764
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