Small-molecule intramimics of formin autoinhibition: a new strategy to target the cytoskeletal remodeling machinery in cancer cells.
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.
Authors' Affiliations: Laboratories of Cell Structure and Signal Integration and Structural Sciences, Van Andel Research Institute; Grand Valley State University, Grand Rapids; and Michigan High Throughput Screening Center, Kalamazoo, Michigan.
L Leanne
LL
Lash
Bradley J
BJ
Wallar
Julie D
JD
Turner
Steven M
SM
Vroegop
Robert E
RE
Kilkuskie
Susan M
SM
Kitchen-Goosen
H Eric
HE
Xu
Arthur S
AS
Alberts
D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D003599:Cytoskeleton / Q000187:drug effects* / Q000378:metabolism; D025461:Feedback, Physiological / Q000187:drug effects*; D005260:Female; D000080865:Formins; D051379:Mice; D008819:Mice, Nude; D008840:Microfilament Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D018716:Molecular Mimicry; D058990:Molecular Targeted Therapy; D041681:NIH 3T3 Cells; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; C108962:DIAPH1 protein, human; D000080865:Formins; D008840:Microfilament Proteins; D054852:Small Molecule Libraries