Biochemical target isolation for novices: affinity-based strategies.

Although a number of genomic and biochemical technologies are now used to elucidate the mechanisms of action of bioactive small molecules, affinity-based isolation of molecular targets is a classic, but still powerful, approach. This review highlights recent cases where biochemical isolation of target proteins of bioactive small molecules highlighted general strategies for a successful isolation and identification of molecular targets. This review is intended to be both an update on the most recent findings for those already active in the field of forward chemical genetics and a guide for scientists entering this burgeoning field.

[1]  Trevor C. Y. Kwok,et al.  A small-molecule screen in C. elegans yields a new calcium channel antagonist , 2006, Nature.

[2]  Tae-Wook Kang,et al.  Facilitated forward chemical genetics using a tagged triazine library and zebrafish embryo screening. , 2003, Journal of the American Chemical Society.

[3]  Stuart L Schreiber,et al.  Identification of a small-molecule inhibitor of class Ia PI3Ks with cell-based screening. , 2007, Chemistry & biology.

[4]  Qihong Huang,et al.  Small-molecule inhibitors of microrna miR-21 function. , 2008, Angewandte Chemie.

[5]  D. Alberts,et al.  Antiproliferative effect of nonsteroidal antiinflammatory drugs against human colon cancer cells. , 1994, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology.

[6]  M. Uesugi,et al.  A wrench-shaped synthetic molecule that modulates a transcription factor-coactivator interaction. , 2004, Journal of the American Chemical Society.

[7]  C. Nguyên,et al.  Chemogenomic identification of Ref-1/AP-1 as a therapeutic target for asthma , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[8]  M. Ueda,et al.  Enantiodifferential approach for the detection of the target membrane protein of the jasmonate glycoside that controls the leaf movement of Albizzia saman. , 2008, Angewandte Chemie.

[9]  S. Schreiber,et al.  Identification of a Class of Small Molecule Inhibitors of the Sirtuin Family of NAD-dependent Deacetylases by Phenotypic Screening* , 2001, The Journal of Biological Chemistry.

[10]  R G Smith,et al.  Discovery of a small molecule insulin mimetic with antidiabetic activity in mice. , 1999, Science.

[11]  T. Owa,et al.  Splicing factor SF3b as a target of the antitumor natural product pladienolide , 2007, Nature Chemical Biology.

[12]  P. Schultz,et al.  Small-molecule synergist of the Wnt/β-catenin signaling pathway , 2007, Proceedings of the National Academy of Sciences.

[13]  S. Schreiber,et al.  A Mammalian Histone Deacetylase Related to the Yeast Transcriptional Regulator Rpd3p , 1996, Science.

[14]  Yoshiya Oda,et al.  Quantitative chemical proteomics for identifying candidate drug targets. , 2003, Analytical chemistry.

[15]  M. Clynes,et al.  Enhancement of chemotherapeutic drug toxicity to human tumour cells in vitro by a subset of non-steroidal anti-inflammatory drugs (NSAIDs). , 1998, European journal of cancer.

[16]  M. Uesugi,et al.  Chemical genetic identification of the histamine H1 receptor as a stimulator of insulin-induced adipogenesis. , 2004, Chemistry & biology.

[17]  D. Austin,et al.  Display cloning: functional identification of natural product receptors using cDNA-phage display. , 1999, Chemistry & biology.

[18]  Xiaodong Wang,et al.  Diazonamide toxins reveal an unexpected function for ornithine δ-amino transferase in mitotic cell division , 2007, Proceedings of the National Academy of Sciences.

[19]  Curzio Rüegg,et al.  Non steroidal anti‐inflammatory drugs and COX‐2 inhibitors as anti‐cancer therapeutics: hypes, hopes and reality , 2003, Annals of medicine.

[20]  M. Caulfield,et al.  Indomethacin and Protein Binding of Methotrexate , 1992, Human & experimental toxicology.

[21]  W. Bornmann,et al.  The anti-angiogenic agent fumagillin covalently binds and inhibits the methionine aminopeptidase, MetAP-2. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[22]  S. Haggarty,et al.  Small molecule inhibitor of mitotic spindle bipolarity identified in a phenotype-based screen. , 1999, Science.

[23]  R. Aebersold,et al.  Mass spectrometry-based proteomics , 2003, Nature.

[24]  R. Lefkowitz,et al.  Identification of the cardiac beta-adrenergic receptor protein: solubilization and purification by affinity chromatography. , 1972, Proceedings of the National Academy of Sciences of the United States of America.

[25]  Hong Ma,et al.  A small molecule inhibitor of beta-catenin/CREB-binding protein transcription [corrected]. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[26]  M. Hagiwara,et al.  Spliceostatin A targets SF3b and inhibits both splicing and nuclear retention of pre-mRNA , 2007, Nature Chemical Biology.

[27]  S. Schreiber,et al.  A receptor for the immuno-suppressant FK506 is a cis–trans peptidyl-prolyl isomerase , 1989, Nature.

[28]  M. Uesugi,et al.  Identification of Bioactive Molecules by Adipogenesis Profiling of Organic Compounds* 210 , 2003, The Journal of Biological Chemistry.

[29]  Z. Paroo,et al.  A small molecule enhances RNA interference and promotes microRNA processing , 2008, Nature Biotechnology.

[30]  Young-Tae Chang,et al.  Dissection of melanogenesis with small molecules identifies prohibitin as a regulator. , 2005, Chemistry & biology.

[31]  Lin Tang,et al.  Roscovitine Targets, Protein Kinases and Pyridoxal Kinase*[boxs] , 2005, Journal of Biological Chemistry.

[32]  Peter G. Schultz,et al.  Synthetic small molecules that control stem cell fate , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[33]  Wei Zhang,et al.  Chemical genetic identification of the IGF-linked pathway that is mediated by STAT6 and MFP2. , 2006, Chemistry & biology.

[34]  M. Uesugi,et al.  Polyproline-rod approach to isolating protein targets of bioactive small molecules: isolation of a new target of indomethacin. , 2007, Journal of the American Chemical Society.

[35]  Stuart L. Schreiber,et al.  Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes , 1991, Cell.

[36]  C. Crews,et al.  Epoxomicin, a potent and selective proteasome inhibitor, exhibits in vivo antiinflammatory activity. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[37]  M. Hull,et al.  Activity of the non-steroidal anti-inflammatory drug indomethacin against colorectal cancer. , 2003, Cancer treatment reviews.

[38]  Jun O. Liu,et al.  Inhibition of eukaryotic translation initiation by the marine natural product pateamine A. , 2005, Molecular cell.

[39]  Y. Feng,et al.  Use of biomimetic diversity-oriented synthesis to discover galanthamine-like molecules with biological properties beyond those of the natural product. , 2001, Journal of the American Chemical Society.