New Chemical Modulators of Cell Migration
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 anticancer drug development, controlling actin dynamics and cell motility as a therapeutic approach has received scant attention in comparison until recently.
The small molecules we screen for anti-migratory and related activities come from multiple sources, including organic synthesis in our lab. The cell migration inhibitors we have identified include locostatin, which targets Raf kinase inhibitor protein, and tetrahydroisoquinoline natural product analogs that target the membrane-cytoskeleton linker protein radixin and the multifunctional carbohydrate-binding protein galectin-3 with different degrees of selectivity. We have also investigated certain synthetic metal-ligand complexes that potently inhibit cell migration, as well as the cucurbitacin family of natural products. Work on other small molecules that affect cell motility is onging. Such compounds may have great potential as research reagents and even cancer chemotherapeutics as agents that inhibit angiogenesis or tumor invasion and metastasis. The same screens also allow us to pick up activities that accelerate wound closure, which again could have potential as research tools and perhaps also as wound healing-promoting agents. This chemical biology approach to cell motility therefore has great promise from a number of perspectives.
Some of the small molecules we have discovered as novel inhibitors of cell migration and whose mechanism of action we are investigating include:
