Melanoma Therapeutic Strategies that Select against Resistance by Exploiting MYC-Driven Evolutionary Convergence.

Diverse pathways drive resistance to BRAF/MEK inhibitors in BRAF-mutant melanoma, suggesting that durable control of resistance will be a challenge. By combining statistical modeling of genomic data from matched pre-treatment and post-relapse patient tumors with functional interrogation of >20 in vitro and in vivo resistance models, we discovered that major pathways of resistance converge to activate the transcription factor, c-MYC (MYC). MYC expression and pathway gene signatures were suppressed following drug treatment, and then rebounded during progression.

Rules of Macrocycle Topology: A [13]-Macrodilactone Case Study.

Shape is an inherent trait of a molecule that dictates how it interacts with other molecules, either in binding events or intermolecular reactions. Large-ring macrocyclic compounds in particular leverage their shape when they are selectively bound by biomolecules and also when they exhibit macrocyclic diastereoselectivity. Nonetheless, rules that link structural parameters to the conformation of a macrocycle are still rudimentary.

Stereogenic α-carbons determine the shape and topology of [13]-macrodilactones.

The synthesis and characterization of new [13]-macrodilactones substituted at stereogenic centers α- to the carbonyl are reported. When one center is substituted, it directs the topology of the macrocycle; when two centers are substituted, both the shape and the topology are influenced. The findings indicate that the number and configuration of α-centers fine-tune macrocyclic structure.

Cardiac glycoside activities link Na(+)/K(+) ATPase ion-transport to breast cancer cell migration via correlative SAR.

The cardiac glycosides ouabain and digitoxin, established Na(+)/K(+) ATPase inhibitors, were found to inhibit MDA-MB-231 breast cancer cell migration through an unbiased chemical genetics screen for cell motility. The Na(+)/K(+) ATPase acts both as an ion-transporter and as a receptor for cardiac glycosides. To delineate which function is related to breast cancer cell migration, structure-activity relationship (SAR) profiles of cardiac glycosides were established at the cellular (cell migration inhibition), molecular (Na(+)/K(+) ATPase inhibition), and atomic (computational docking) levels.

De novo macrolide-glycolipid macrolactone hybrids: Synthesis, structure and antibiotic activity of carbohydrate-fused macrocycles.

Natural product-like macrocycles were designed as potential antibacterial compounds. The macrocycles featured a D-glucose unit fused into a 12- or 13-member macrolactone. The rings are connected via the C6' and anomeric (C1') positions of the monosaccharide.

Raf kinase inhibitor protein suppresses nuclear factor-κB-dependent cancer cell invasion through negative regulation of matrix metalloproteinase expression.

Accumulating evidence suggests that Raf kinase inhibitor protein (RKIP), which negatively regulates multiple signaling cascades including the Raf and nuclear factor-κB (NF-κB) pathways, functions as a metastasis suppressor. However, the basis for this activity is not clear. We investigated this question in a panel of breast cancer, colon cancer and melanoma cell lines.

Synthesis and evaluation of antimigratory and antiproliferative activities of lipid-linked [13]-macro-dilactones.

The biological activities of a family of novel, lipid-linked 13-membered-ring macro-dilactones are reported. These [13]-macro-dilactones were synthesized by diacylation of functionalized diols, followed by ring-closing metathesis under conditions we had previously reported. Antimigratory, cytostatic and cytotoxic activities of the compounds against cancer cells were evaluated.