D. Fong

TL;DR: PLX4720, a 7-azaindole derivative that inhibits B-RafV600E with an IC50 of 13 nM, defines a class of kinase inhibitor with marked selectivity in both biochemical and cellular assays and represents the entire discovery process from initial identification through structural and biological studies in animal models to a promising therapeutic for testing in cancer patients bearing B- RafV 600E-driven tumors.

TL;DR: Structural insights will enable the design of isoform-selective inhibitors with improved binding affinity and should facilitate the discovery of more potent and selective PDE inhibitors for the treatment of a variety of diseases.

TL;DR: Next-generation RAF inhibitors are identified (dubbed ‘paradox breakers’) that suppress mutant BRAF cells without activating the MAPK pathway in cells bearing upstream activation, a concept currently undergoing human clinical evaluation with PLX8394.

TL;DR: In this paper, the authors describe the mechanism of nucleotide selectivity on the basis of high-resolution co-crystal structures of three types of PDEs: cAMP-specific, cGMP-specific and dual-specific.

TL;DR: The structure of the PDE1B structure shows that in dual-specific PDEs a key histidine residue may enable the invariant glutamine to toggle between cAMP and cGMP, and the structural understanding of nucleotide binding enables the design of new PDE inhibitors that may treat diseases in which cyclic nucleotides play a critical role.