Introduction 4641 1.1. Going in for Protein−Protein Interactions and Pathways 4641 1.2. Protein−Protein Interactions and Small Molecules 4641 2. Case Study 1: Tubulin Polymerization and Natural Product-Derived Small Molecules 4642 3. Case Study 2: p53 and MDM2 Interactions and Small Molecules 4649 3.1. Natural Product Inhibitors of p53−MDM2 Interactions 4650 3.2. β-Hairpin Peptidomimetics 4652 3.3. Terphenyls 4653 3.4. Nutlins 4653 3.5. Benzodiazepines 4654 3.6. Spiro-oxindoles 4656 3.7. Chromenotriazolopyrimidines 4656 3.8. Piperidinones 4657 3.9. Indolo-imidazoles 4658 4. Case Study 3: Modulation of HSP90-Related Protein−Protein Interactions by Natural Products and Related Compounds 4659 4.1. Structure, Conformation, and Functions of HSP 4659 4.2. Hsp90 Inhibitors 4660 5. Case Study 4: Protein−Protein Interactions Centered on the Inhibitors of Apoptosis Proteins (IAPs) and Synthetic Small Molecules 4666 5.1.

No abstract

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 actintargeting marine macrolide that can suppress proliferation, migration, and invasion of breast and ovarian cancer cells at low nanomolar doses. Through structure−activity relationship studies focused on the actin-binding tail region (C24−C35) of MycB, we identified a potent truncated derivative that inhibits polymerization of G-actin and severs F-actin by binding to actin's barbed end cleft. Biological analyses of this miniature MycB derivative demonstrate that it causes a rapid collapse of the actin cytoskeleton in ovarian cancer cells and impairs cancer cell motility and invasion of the extracellular matrix (ECM) by inhibiting invadopodia-mediated ECM degradation. These studies provide essential proof-of-principle for developing actin-targeting therapeutic agents to block cancer metastasis and establish a synthetically tractable barbed end-binding pharmacophore that can be further improved by adding targeting groups for precision drug design.