Kinase inhibitors are a new class of therapeutics with a propensity to inhibit multiple targets. The biological consequences of multi-kinase activity are poorly defined, and an important step toward understanding the relationship between selectivity, efficacy and safety is the exploration of how inhibitors interact with the human kinome. We present interaction maps for 38 kinase inhibitors across a panel of 317 kinases representing >50% of the predicted human protein kinome. The data constitute the most comprehensive study of kinase inhibitor selectivity to date and reveal a wide diversity of interaction patterns. To enable a global analysis of the results, we introduce the concept of a selectivity score as a general tool to quantify and differentiate the observed interaction patterns. We further investigate the impact of panel size and find that small assay panels do not provide a robust measure of selectivity.

Three's not always a crowd: A three‐component reaction involving α,β‐unsaturated enones 1, aldehydes 2, and alkenyl zirconium species 3 in the presence of a Rh–binap catalyst leads, sequentially, to aldols 4, enones 5, and 2,3‐disubstituted cycloalkanones 6 in good yields and with high ee values.

The total synthesis of the originally assigned structure of vannusal B (2) and its diastereomer (d-2) are described. Initial forays into these structures with model systems revealed the viability of a metathesis-based approach and a SmI 2 -mediated strategy for the key cyclization to forge the central region of the molecule, ring C. The former approach was abandoned in favor of the latter when more functionalized substrates failed to enter the cyclization process. The successful, devised convergent strategy based on the SmI 2 -mediated ring closure utilized vinyl iodide (−)-26 and aldehyde fragment (±)-86 as key building blocks, whose lithium-mediated coupling led to isomeric coupling products (+)-87 and (−)-88. These intermediates were separately converted to precursors (+)-25 and (−)-97, which cyclized under the influence of SmI 2 -HMPA to afford products (−)-90/(−)-91 and (+)-98, respectively. The former two intermediates were converted to vannusal B structure 2 while the latter gave rise to its diastereomeric structure d-2, neither of which exhibited the reported spectroscopic data of the natural product. These investigations led to the discovery and development of a number of new synthetic technologies that set the stage for the solution of the vannusal structural conundrum.

Mutations in the BRAF gene have been identified in approximately 7% of cancers, including 60% to 70% of melanomas, 29% to 83% of papillary thyroid carcinomas, 4% to 16% colorectal cancers, and a lesser extent in serous ovarian and non-small cell lung cancers. The V600E mutation is found in the vast majority of cases and is an activating mutation, conferring transforming and immortalization potential to cells. CEP-32496 is a potent BRAF inhibitor in an in vitro binding assay for mutated