Toward a Template for Synthetic Actin-Targeting Macrolide Analogues That Inhibit Cancer Cell Invasiveness.

Actin barbed end-binding macrolides have been shown to inhibit cancer cell motility and invasion of extracellular matrix (ECM), evoking their potential utility as therapies for metastatic cancers. Unfortunately, the direct use of these compounds in clinical settings is impeded by their limited natural abundance, challenging total synthesis, and detrimental effects on normal tissues. To develop potent analogues of these compounds that are simpler to synthesize and compatible with cell-specific targeting systems, such as antibodies, we designed over 20 analogues of the acyclic side chain (tail) of the macrolide Mycalolide B.

Truncated Actin-Targeting Macrolide Derivative Blocks Cancer Cell Motility and Invasion of Extracellular Matrix.

Cancer metastasis is a complex process involving highly motile tumor cells that breach tissue barriers, enter the bloodstream and lymphatic system, and disseminate throughout the body as circulating tumor cells. The primary cellular mechanism contributing to these critical events is the reorganization of the actin cytoskeleton. Mycalolide B (MycB) is an actin-targeting marine macrolide that can suppress proliferation, migration, and invasion of breast and ovarian cancer cells at low nanomolar doses.

Structural Studies of Multidrug Resistance Protein 1 Using "Almost" Cysless Template.

Multidrug resistance protein, MRP1 (ABCC1) is a broad-spectrum ATP-binding cassette transporter that plays a major role in defense against dietary and environmental toxicants, in addition to contributing toward multidrug resistance of certain types of malignancy. Elucidating the molecular structure of hMRP1 is key to determining its mechanism of substrate recognition and transport. Here, we report the first successful attempt using cysteine-scanning mutagenesis coupled with cross-linking studies to probe the structure of hMRP1 in its native environment of the cell membrane or in membrane vesicles.