Small-Molecule Inhibitors of Actin Dynamics and Cell Motility

Abstract

Cell motility is a central feature of a range of normal and pathological processes, including embryonic development, tissue repair, immune cell function, angiogenesis, and cancer metastasis. The dynamics of the actin cytoskeleton power cell migration. A large number of proteins are known or suspected to play roles in regulating actin dynamics. While there are now many available small molecules that target the actin cytoskeleton directly, there is a paucity of specific inhibitors of actin-binding proteins and other immediate regulators of actin dynamics and cell movement. This makes the field of exceptional interest as a meeting place between the goals of chemical biology and the needs of cell biology. Furthermore, while regulators of the cell cycle have been recognized for some time as targets for anti-cancer drug development, controlling actin dynamics and cell motility as a therapeutic approach has received scant attention in comparison until recently. This review deals with small-molecule inhibitors of actin dynamics as they relate to cell shape change and motility, from compounds targeting actin directly to those targeting proteins involved in the fundamental control of the actin cytoskeleton.

Disruption of Cortical Actin in Skeletal Muscle Demonstrates an Essential Role of the Cytoskeleton in Glucose Transporter 4 Translocation in Insulin-sensitive Tissues

“…Recently, numerous studies have provided evidence that cytoskeletal mechanics play an essential role in the translocation of GLUT4 to the plasma membrane (22,23,39,(52)(53)(54)(55)(56)(57)(58). In particular, pharmacological disruption of cortical F-actin causes a profound disturbance in GLUT4 translocation and glucose transport (23,55,59). Although these data are consistent with the conclusion that the cellular cytoskeleton is involved in the translocation of GLUT4 to the plasma membrane, they have all been carried out in cultured cell model systems.…”

Structures of microfilament destabilizing toxins bound to actin provide insight into toxin design and activity

“…Small molecule marine natural products that target actin filaments with high affinity and potently interfere with actin filament dynamics have been shown to display cytotoxicity against several forms of multidrug resistant tumors (2)(3)(4)(5)(6)(7). For this reason, their candidacy as clinical chemotherapeutic treatments has gained significant attention (8).…”

Developmental Biology of Neoplastic Growth

“…Therefore, small molecules whose modes of action on actin are different from cytochalasins were required. During the last 20 years a large number of highly cytotoxic compounds were isolated from marine organisms (König et al 2006;Nagle et al 2006), and quite a few of these have been shown to affect actin filaments (Spector et al 1999;Fenteany and Zhu 2003). Interestingly, the majority of them mimic endogenous actin-binding proteins (McGough et al 2003;Silacci et al 2004).…”

“…Natural product inhibitors of actin cytoskeleton dynamics are not only recognized as valuable molecular probes for dissecting complex mechanisms of cellular function, but also their potential use as chemotherapeutics has become a focus of scientific investigation. Cytoskeletal inhibitors are lethal to tumor cells and several of them have been included in the National Cancer Institute's Molecular Targets Development Program (Fenteany and Zhu 2003;Spector et al 1999). So far, however, no actin-binding drugs have entered clinical trials due to their lack of selectivity for diseased cells.…”

“…Similarly, while there are numerous tubulin-targeted natural products used in basic or clinical sciences, fewer molecules are identified as targeting tubulin-binding proteins. This makes the study of actin and tubulin regulatory molecules of exceptional interest to chemical biologists and cell biologists (Fenteany and Zhu 2003).…”