One-third of all human cancers harbor somatic RAS mutations. This leads to aberrant activation of downstream signaling pathways involving the RAF kinases. Current ATP-competitive RAF inhibitors are active in cancers with somatic RAF mutations, such as BRAF(V600) mutant melanomas. However, they paradoxically promote the growth of RAS mutant tumors, partly due to the complex interplay between different homo- and heterodimers of A-RAF, B-RAF, and C-RAF. Based on pathway analysis and structure-guided compound identification, we describe the natural product cotylenin-A (CN-A) as stabilizer of the physical interaction of C-RAF with 14-3-3 proteins. CN-A binds to inhibitory 14-3-3 interaction sites of C-RAF, pSer233, and pSer259, but not to the activating interaction site, pSer621. While CN-A alone is inactive in RAS mutant cancer models, combined treatment with CN-A and an anti-EGFR antibody synergistically suppresses tumor growth in vitro and in vivo. This defines a novel pharmacologic strategy for treatment of RAS mutant cancers.

Dendrimers have several unique properties that make them attractive scaffolds for use in biomedical applications. To date, multivalent and multimodal dendritic structures have been synthesized predominantly by statistical modification of peripheral groups. However, the potential application of such probes in patients demands well-defined and monodisperse materials that have unique structures. Current progress in the field of chemical biology, in particular chemoselective ligation methods, renders this challenge possible. In this Minireview, we outline the different available synthetic strategies, some applications that already make use of this new generation of multivalent and multimodal architectures, and the challenges for future developments.

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