title: Development of a large-scale chemogenomics database to improve drug candidate selection and to understand mechanisms of chemical toxicity and action.
abstract: Successful drug discovery requires accurate decision making in order to advance the best candidates from initial lead identification to final approval. Chemogenomics, the use of genomic tools in pharmacology and toxicology, offers a promising enhancement to traditional methods of target identification/validation, lead identification, efficacy evaluation, and toxicity assessment. To realize the value of chemogenomics information, a contextual database is needed to relate the physiological outcomes induced by diverse compounds to the gene expression patterns measured in the same animals. Massively parallel gene expression characterization coupled with traditional assessments of drug candidates provides additional, important mechanistic information, and therefore a means to increase the accuracy of critical decisions. A large-scale chemogenomics database developed from in vivo treated rats provides the context and supporting data to enhance and accelerate accurate interpretation of mechanisms of toxicity and pharmacology of chemicals and drugs. To date, approximately 600 different compounds, including more than 400 FDA approved drugs, 60 drugs approved in Europe and Japan, 25 withdrawn drugs, and 100 toxicants, have been profiled in up to 7 different tissues of rats (representing over 3200 different drug-dose-time-tissue combinations). Accomplishing this task required evaluating and improving a number of in vivo and microarray protocols, including over 80 rigorous quality control steps. The utility of pairing clinical pathology assessments with gene expression data is illustrated using three anti-neoplastic drugs: carmustine, methotrexate, and thioguanine, which had similar effects on the blood compartment, but diverse effects on hepatotoxicity. We will demonstrate that gene expression events monitored in the liver can be used to predict pathological events occurring in that tissue as well as in hematopoietic tissues.
authors: Iconix Pharmaceuticals, 325 E. Middlefield Road, Mountain View, CA 94043, USA. bganter@iconixpharm.com
authors: Brigitte
authors: B
authors: Ganter
authors: Stuart
authors: S
authors: Tugendreich
authors: Cecelia I
authors: CI
authors: Pearson
authors: Eser
authors: E
authors: Ayanoglu
authors: Susanne
authors: S
authors: Baumhueter
authors: Keith A
authors: KA
authors: Bostian
authors: Lindsay
authors: L
authors: Brady
authors: Leslie J
authors: LJ
authors: Browne
authors: John T
authors: JT
authors: Calvin
authors: Gwo-Jen
authors: GJ
authors: Day
authors: Naiomi
authors: N
authors: Breckenridge
authors: Shane
authors: S
authors: Dunlea
authors: Barrett P
authors: BP
authors: Eynon
authors: L Mike
authors: LM
authors: Furness
authors: Joe
authors: J
authors: Ferng
authors: Mark R
authors: MR
authors: Fielden
authors: Susan Y
authors: SY
authors: Fujimoto
authors: Li
authors: L
authors: Gong
authors: Christopher
authors: C
authors: Hu
authors: Radha
authors: R
authors: Idury
authors: Michael S B
authors: MS
authors: Judo
authors: Kyle L
authors: KL
authors: Kolaja
authors: May D
authors: MD
authors: Lee
authors: Christopher
authors: C
authors: McSorley
authors: James M
authors: JM
authors: Minor
authors: Ramesh V
authors: RV
authors: Nair
authors: Georges
authors: G
authors: Natsoulis
authors: Peter
authors: P
authors: Nguyen
authors: Simone M
authors: SM
authors: Nicholson
authors: Hang
authors: H
authors: Pham
authors: Alan H
authors: AH
authors: Roter
authors: Dongxu
authors: D
authors: Sun
authors: Siqi
authors: S
authors: Tan
authors: Silke
authors: S
authors: Thode
authors: Alexander M
authors: AM
authors: Tolley
authors: Antoaneta
authors: A
authors: Vladimirova
authors: Jian
authors: J
authors: Yang
authors: Zhiming
authors: Z
authors: Zhou
authors: Kurt
authors: K
authors: Jarnagin
mesh_terms: D000624:5-Aminolevulinate Synthetase / Q000096:biosynthesis; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000633:toxicity; D001331:Automation; D001652:Bile Ducts / Q000473:pathology; D001709:Biotechnology / Q000379:methods*; D002330:Carmustine / Q000633:toxicity; D019295:Computational Biology; D019992:Databases as Topic; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D015195:Drug Design; D004345:Drug Industry / Q000379:methods*; D015870:Gene Expression; D006801:Humans; D006965:Hyperplasia / Q000209:etiology; D008099:Liver / Q000187:drug effects; D008297:Male; D008727:Methotrexate / Q000633:toxicity; D009693:Nucleic Acid Hybridization; D020411:Oligonucleotide Array Sequence Analysis; D009929:Organ Size; D010600:Pharmacology / Q000379:methods; D012313:RNA / Q000737:chemistry; D018075:RNA, Complementary / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012156:Reticulocytes / Q000166:cytology / Q000378:metabolism; D013866:Thioguanine / Q000633:toxicity; D013997:Time Factors; D014018:Tissue Distribution; D014116:Toxicology / Q000379:methods
chemical_list: D000970:Antineoplastic Agents; D018075:RNA, Complementary; D012313:RNA; D000624:5-Aminolevulinate Synthetase; C480079:ALAS2 protein, human; D013866:Thioguanine; D002330:Carmustine; D008727:Methotrexate