ABSTRACT
Although the cancer cell cytoskeleton is a clinically validated target, few new strategies have emerged for selectively targeting cell division by modulating the cytoskeletal structure, particularly ways that could avoid the cardiotoxic and neurotoxic effects of current agents such as taxanes. We address this gap by describing a novel class of small-molecule agonists of the mammalian Diaphanous (mDia)-related formins, which act downstream of Rho GTPases to assemble actin filaments, and their organization with microfilaments to establish and maintain cell polarity during migration and asymmetric division. GTP-bound Rho activates mDia family members by disrupting the interaction between the DID and DAD autoregulatory domains, which releases the FH2 domain to modulate actin and microtubule dynamics. In screening for DID-DAD disruptors that activate mDia, we identified two molecules called intramimics (IMM-01 and -02) that were sufficient to trigger actin assembly and microtubule stabilization, serum response factor-mediated gene expression, cell-cycle arrest, and apoptosis. In vivo analysis of IMM-01 and -02 established their ability to slow tumor growth in a mouse xenograft model of colon cancer. Taken together, our work establishes the use of intramimics and mDia-related formins as a new general strategy for therapeutic targeting of the cytoskeletal remodeling machinery of cancer cells.
Subject(s)
Adaptor Proteins, Signal Transducing/antagonists & inhibitors , Antineoplastic Agents/therapeutic use , Cytoskeleton/drug effects , Feedback, Physiological/drug effects , Microfilament Proteins/antagonists & inhibitors , Molecular Mimicry , Neoplasms/drug therapy , Adaptor Proteins, Signal Transducing/chemistry , Animals , Antineoplastic Agents/pharmacology , Cytoskeleton/metabolism , Female , Formins , Mice , Mice, Nude , Microfilament Proteins/chemistry , Molecular Targeted Therapy , NIH 3T3 Cells , Neoplasms/metabolism , Small Molecule Libraries/chemistry , Small Molecule Libraries/pharmacology , Tumor Cells, Cultured , Xenograft Model Antitumor AssaysABSTRACT
A novel series of nonnucleoside HCV NS5B polymerase inhibitors were prepared from (2Z)-2-(benzoylamino)-3-(5-phenyl-2-furyl)acrylic acid, a high throughput screening lead. SAR studies combined with structure based drug design focusing on the southern heterobiaryl region of the template led to the synthesis of several potent and orally bioavailable lead compounds. X-ray crystallography studies were also performed to understand the interaction of these inhibitors with HCV NS5B polymerase.
Subject(s)
Acrylates/pharmacology , Enzyme Inhibitors/pharmacology , Furans/pharmacology , Viral Nonstructural Proteins/antagonists & inhibitors , Acrylates/chemistry , Acrylates/pharmacokinetics , Biological Availability , Crystallography, X-Ray , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacokinetics , Furans/chemistry , Furans/pharmacokinetics , Structure-Activity RelationshipABSTRACT
A novel series of non-nucleoside HCV NS5B polymerase inhibitors was prepared from a (2Z)-2-benzoylamino-3-(4-phenoxy-phenyl)-acrylic acid template. Solution and solid phase analog synthesis focused on the northern region of the template combined with structure based design led to the discovery of several potent and orally bioavailable lead compounds.