The advent of powerful genomics technologies has uncovered many fundamental aspects of biology, including the mechanisms of cancer; however, it has not been appropriately matched by the development of global approaches to discover new medicines against human diseases. Here we describe a unique high-throughput screening strategy by high-throughput sequencing, referred to as HTS 2 , to meet this challenge. This technology enables large-scale and quantitative analysis of gene matrices associated with specific disease phenotypes, therefore allowing screening for small molecules that can specifically intervene with disease-linked gene-expression events. By initially applying this multitarget strategy to the pressing problem of hormone-refractory prostate cancer, which tends to be accelerated by the current antiandrogen therapy, we identify Peruvoside, a cardiac glycoside, which can potently inhibit both androgen-sensitive and -resistant prostate cancer cells without triggering severe cytotoxicity. We further show that, despite transcriptional reprogramming in prostate cancer cells at different disease stages, the compound can effectively block androgen receptor-dependent gene expression by inducing rapid androgen receptor degradation via the proteasome pathway. These findings establish a genomics-based phenotypic screening approach capable of quickly connecting pathways of phenotypic response to the molecular mechanism of drug action, thus offering a unique pathway-centric strategy for drug discovery.chemical screening | gene signature I t is of utmost importance to match the power of functional genomics in interrogating diseased cells/tissues with potent drug-discovery approaches. Although target-centric approaches have been favored in the past decade, phenotypic screening appears to have out-paced such mechanism-based screening strategies in discovering "first-in-class" drugs, thus igniting recent debate on the merit of target-based strategies (1). This debate is important because analysis of US Food and Drug Administration-approved drugs in recent decades have revealed low productivity in drug research and development, despite staggering investment in the pharmaceutical industry (2).Although phenotypic approaches score the final functional outcomes, it is challenging to optimize candidate drugs without knowing their mechanism of action and many procedures have limited capacity in implementing high-throughput screening. In contrast, target-centric approaches have their own problems because specific molecular hypotheses based on the existing knowledge may or may not be related to disease phenotype. A proposed solution to these problems is to monitor the collective response of all relevant genes to a specific disease phenotype (3), but this has been a major challenge with any existing technologies.A "quick-win/fast-fail" strategy has been proposed to streamline initial candidate hits in early phases to offset high attrition rates in drug discovery (4). This strategy begs the question of how to retain the advantages o...

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A chiral Lewis acid-promoted cyclopropanation using a phenyliodonium ylide as the carbene precursor was developed. An EPR spectroscopy study supported a stepwise biradical mechanism.

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