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Genomes and GenesSpecies | Ker YuSummaryAffiliation: Wyeth Research Country: USA Publications
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Publications
Novel sulfur-containing rapamycin analogs prepared by precursor-directed biosynthesisEdmund I Graziani
Department of Chemical and Screening Sciences, Wyeth Research, 401 North Middletown Road, Pearl River, New York 10965, USA
Org Lett 5:2385-8. 2003..The structures of the two new compounds, 20-thiarapamycin (2) and 15-deoxo-19-sulfoxylrapamycin (3), were determined by spectroscopic methods...
Production of novel rapamycin analogs by precursor-directed biosynthesisFrank V Ritacco
Natural Products, Wyeth Research, 401 North Middletown Road, Building 205, Room 465, Pearl River, NY 10965, USA
Appl Environ Microbiol 71:1971-6. 2005..We describe here the use of this method for production of two new sulfur-containing rapamycin analogs, 20-thiarapamycin and 15-deoxo-19-sulfoxylrapamycin, and report measurement of their binding to FKBP12...
Beyond rapalog therapy: preclinical pharmacology and antitumor activity of WYE-125132, an ATP-competitive and specific inhibitor of mTORC1 and mTORC2Ker Yu
Discovery Oncology and Discovery Medicinal Chemistry, Wyeth Research, Pearl River, New York 10965, USA
Cancer Res 70:621-31. 2010....- PWT-458, a novel pegylated-17-hydroxywortmannin, inhibits phosphatidylinositol 3-kinase signaling and suppresses growth of solid tumorsKer Yu
Department of Oncology Research, Wyeth Research, Pearl River, NY, USA
Cancer Biol Ther 4:538-45. 2005..These studies identify PWT-458 as an effective anticancer agent and provide strong proof-of-principle for targeting the PI3K pathway as novel anticancer therapy... - Biochemical, cellular, and in vivo activity of novel ATP-competitive and selective inhibitors of the mammalian target of rapamycinKer Yu
Discovery Oncology, Wyeth Research, Pearl River, New York 10965, USA
Cancer Res 69:6232-40. 2009.... - Response and determinants of cancer cell susceptibility to PI3K inhibitors: combined targeting of PI3K and Mek1 as an effective anticancer strategyKer Yu
Discovery Oncology, Wyeth Research, Pearl River, New York 10965, USA
Cancer Biol Ther 7:307-15. 2008..Our results identify deregulation of the Ras/Raf/Mek/ERK pathway as a dominant determinant in cancer cell resistance to PI3K inhibitors and highlight combined targeting of PI3K and Mek1 as an effective anticancer strategy... - ATP-competitive inhibitors of the mammalian target of rapamycin: design and synthesis of highly potent and selective pyrazolopyrimidinesArie Zask
Wyeth Research, 401 N Middletown Road, Pearl River, NY 10965, USA
J Med Chem 52:5013-6. 2009..Structural features leading to potency and selectivity were identified and refined leading to compounds with in vivo efficacy in tumor xenograft models... - Synthesis and SAR of novel 4-morpholinopyrrolopyrimidine derivatives as potent phosphatidylinositol 3-kinase inhibitorsZecheng Chen
Chemical Sciences, Wyeth Research, 401 N Middletown Road, Pearl River, New York 10965, USA
J Med Chem 53:3169-82. 2010..g., the phosphorylation of Akt at Thr308 (T308) and Ser473 (S473)] in the human breast cancer cell line MDA361. In addition, compound 46 demonstrated good in vivo efficacy in the MDA361 human breast tumor xenograft model... - Hybrid inhibitors of phosphatidylinositol 3-kinase (PI3K) and the mammalian target of rapamycin (mTOR): design, synthesis, and superior antitumor activity of novel wortmannin-rapamycin conjugatesSemiramis Ayral-Kaloustian
Discovery Medicinal Chemistry, Wyeth Research, 401 North Middletown Road, Pearl River, New York 10965, USA
J Med Chem 53:452-9. 2010..Thus, we have uncovered a novel approach to target both PI3K and mTOR via hybrid inhibitors, leading to a broader and more robust anticancer efficacy... - Incorporation of water-solubilizing groups in pyrazolopyrimidine mTOR inhibitors: discovery of highly potent and selective analogs with improved human microsomal stabilityDavid J Richard
Chemical Sciences, Wyeth Research, 401 N Middletown Rd, Pearl River, NY 10965, USA
Bioorg Med Chem Lett 19:6830-5. 2009.... - Discovery of 4-morpholino-6-aryl-1H-pyrazolo[3,4-d]pyrimidines as highly potent and selective ATP-competitive inhibitors of the mammalian target of rapamycin (mTOR): optimization of the 6-aryl substituentJeroen C Verheijen
Wyeth Research, Pearl River, NY 10965, USA
J Med Chem 52:8010-24. 2009..These compounds combined potent mTOR inhibition (IC(50) < 1 nM) with unprecedented activity in cellular proliferation assays (IC(50) < 1 nM)... - Discovery of 3,6-dihydro-2H-pyran as a morpholine replacement in 6-aryl-1H-pyrazolo[3,4-d]pyrimidines and 2-arylthieno[3,2-d]pyrimidines: ATP-competitive inhibitors of the mammalian target of rapamycin (mTOR)Joshua Kaplan
Chemical Sciences, Wyeth Research, 401 N Middletown Road, Pearl River, NY 10965, United States
Bioorg Med Chem Lett 20:640-3. 2010..These results establish the DHP group as a hinge-region binding motif for the preparation of highly potent and selective mTOR inhibitors... - Discovery and optimization of 2-(4-substituted-pyrrolo[2,3-b]pyridin-3-yl)methylene-4-hydroxybenzofuran-3(2H)-ones as potent and selective ATP-competitive inhibitors of the mammalian target of rapamycin (mTOR)Hwei Ru Tsou
Chemical Sciences, Wyeth Research, 401 N Middletown Road, Pearl River, NY 10965, United States
Bioorg Med Chem Lett 20:2321-5. 2010..An X-ray co-crystal structure of one inhibitor with the mTOR-related PI3Kgamma revealed the key hydrogen bonding interactions... - Bis(morpholino-1,3,5-triazine) derivatives: potent adenosine 5'-triphosphate competitive phosphatidylinositol-3-kinase/mammalian target of rapamycin inhibitors: discovery of compound 26 (PKI-587), a highly efficacious dual inhibitorAranapakam M Venkatesan
Chemical Sciences, Wyeth Research, 401 N Middletown Road, Pearl River, New York 10965, USA
J Med Chem 53:2636-45. 2010..The structure-activity relationships and the in vitro and in vivo activity of analogues in this series are described... - Pyrazolopyrimidines as highly potent and selective, ATP-competitive inhibitors of the mammalian target of rapamycin (mTOR): optimization of the 1-substituentKevin J Curran
Chemical Sciences, Wyeth Research, 401 N Middletown Rd, Pearl River, NY 10965, USA
Bioorg Med Chem Lett 20:1440-4. 2010.... - Lead optimization of N-3-substituted 7-morpholinotriazolopyrimidines as dual phosphoinositide 3-kinase/mammalian target of rapamycin inhibitors: discovery of PKI-402Christoph M Dehnhardt
Discovery Medicinal Chemistry, Wyeth Research, Pearl River, New York 10965, USA
J Med Chem 53:798-810. 2010..In addition, 3 showed excellent in vivo efficacy in various human cancer xenografts, validating suppression of PI3K/mTOR signaling as a potential anticancer therapy... - Discovery of 2-ureidophenyltriazines bearing bridged morpholines as potent and selective ATP-competitive mTOR inhibitorsArie Zask
Chemical Sciences, Wyeth Research, Pearl River, NY 10965, USA
Bioorg Med Chem Lett 20:2644-7. 2010..Potency and selectivity was demonstrated both in vitro and in vivo through biomarker suppression studies. Select compounds exhibited potent inhibition of tumor growth in nude mouse xenograft assays upon PO and IV administration... - 5-ureidobenzofuranone indoles as potent and efficacious inhibitors of PI3 kinase-alpha and mTOR for the treatment of breast cancerNan Zhang
Discovery Medicinal Chemistry, Wyeth Research, Pearl River, NY 10965, USA
Bioorg Med Chem Lett 20:3526-9. 2010..It was able to inhibit the biomarker phosphorylation for 8h when dosed at 25 mg/kg iv. In the MDA-MB-361 breast cancer model, it shrank the tumor size remarkably when dosed at 25 mg/kg iv on days 1, 5, and 9... - Discovery of potent and selective inhibitors of the mammalian target of rapamycin (mTOR) kinasePawel Nowak
Chemical Sciences, Wyeth Research, 401 N Middletown Road, Pearl River, New York 10965, USA
J Med Chem 52:7081-9. 2009..These pyrazolopyrimidines represent an exciting new series of mTOR-selective inhibitors with potential for development for cancer therapy... - Morpholine derivatives greatly enhance the selectivity of mammalian target of rapamycin (mTOR) inhibitorsArie Zask
Chemical Sciences, Wyeth Research, Pearl River, NY 10965, USA
J Med Chem 52:7942-5. 2009..Molecular modeling suggests that a single amino acid difference between PI3K and mTOR (Phe961Leu) accounts for the profound selectivity seen by creating a deeper pocket in mTOR that can accommodate bridged morpholines... - Novel imidazolopyrimidines as dual PI3-Kinase/mTOR inhibitorsAranapakam M Venkatesan
Chemical Sciences, Wyeth Research, Pearl River, NY 10965, United States
Bioorg Med Chem Lett 20:653-6. 2010..These compounds were found to be ATP competitive with good tumor cell growth inhibition, and suppression of pathway specific biomakers such as phosphorylation of Akt at T308... - PKI-179: an orally efficacious dual phosphatidylinositol-3-kinase (PI3K)/mammalian target of rapamycin (mTOR) inhibitorAranapakam M Venkatesan
Chemical Sciences, PGRD, Pfizer Inc, Legacy Wyeth Research, 401 N Middletown Rd, Pearl River, NY 10965, USA
Bioorg Med Chem Lett 20:5869-73. 2010..2.1]octane and reduction of the molecular weight yielded 8m (PKI-179), an orally efficacious dual PI3-kinase/mTOR inhibitor. The in vitro activity, in vivo efficacy, and PK properties of 8m are discussed... - Identification of 2-oxatriazines as highly potent pan-PI3K/mTOR dual inhibitorsChristoph M Dehnhardt
Medicinal Chemistry, Pfizer, 401 N Middletown Rd, Pearl River, NY 10965, USA
Bioorg Med Chem Lett 21:4773-8. 2011..Some 2-oxatriazines showed promising in vivo biomarker suppression and induced apoptosis in the MDA-MB-361 breast cancer xenograft model... - Pegylated wortmannin and 17-hydroxywortmannin conjugates as phosphoinositide 3-kinase inhibitors active in human tumor xenograft modelsTianmin Zhu
Preclinical Development, Wyeth Research, 401 North Middletown Road, Pearl River, New York 10965, USA
J Med Chem 49:1373-8. 2006..Pegylation of wortmannin and 17-hydroxywortmannin gives rise to conjugates with improved properties, including a higher therapeutic index. Pegylated 17-hydroxywortmannin (8, PWT-458) has been selected for further development... - A new pharmacologic action of CCI-779 involves FKBP12-independent inhibition of mTOR kinase activity and profound repression of global protein synthesisBoris Shor
Discovery Oncology, Wyeth Research, Pearl River, NY 10965, USA
Cancer Res 68:2934-43. 2008..This distinctive high-dose drug effect could be directly related to the antitumor activities of CCI-779 and other rapalogues in human cancer patients... - Discovery of lactoquinomycin and related pyranonaphthoquinones as potent and allosteric inhibitors of AKT/PKB: mechanistic involvement of AKT catalytic activation loop cysteinesLourdes Toral Barza
Oncology Research, Wyeth Research, Pearl River, NY 10965, USA
Mol Cancer Ther 6:3028-38. 2007..Moreover, lactoquinomycin reduced cellular mammalian target of rapamycin signaling and cap-dependent mRNA translation initiation. Our results highlight T-loop targeting as a new strategy for the generation of selective AKT inhibitors... - Targeting mTOR globally in cancer: thinking beyond rapamycinBoris Shor
Discovery Oncology, Wyeth Research, Pearl River, NY, USA
Cell Cycle 8:3831-7. 2009..A more complete suppression of mTOR global signaling network by the new inhibitors is expected to yield a deeper and broader antitumor response in the clinic... - Synthesis and structure-activity relationships of ring-opened 17-hydroxywortmannins: potent phosphoinositide 3-kinase inhibitors with improved properties and anticancer efficacyArie Zask
Wyeth Research, Pearl River, New York 10965, USA
J Med Chem 51:1319-23. 2008..Ring-opened analogues such as compound 13 containing basic amine groups have significantly increased PI3K inhibitory potency and greater efficacy in nude mouse xenograft assays... - 4-Substituted-7-azaindoles bearing a ureidobenzofuranone moiety as potent and selective, ATP-competitive inhibitors of the mammalian target of rapamycin (mTOR)Hwei Ru Tsou
Chemical Sciences, Wyeth Research, 401 N Middletown Road, Pearl River, NY 10965, United States
Bioorg Med Chem Lett 20:2259-63. 2010..Furthermore, modeling showed that the ureido group is best situated at C-5 of the benzofuranone. Syntheses of 4-ureido and 5-ureidobenzofuranones are presented... - Discovery of 2-arylthieno[3,2-d]pyrimidines containing 8-oxa-3-azabi-cyclo[3.2.1]octane in the 4-position as potent inhibitors of mTOR with selectivity over PI3KJeroen C Verheijen
Chemical Sciences, Wyeth Research, 401 N Middletown Rd, Pearl River, NY 10965, USA
Bioorg Med Chem Lett 20:375-9. 2010.... - Identification and characterization of a constitutively T-loop phosphorylated and active recombinant S6K1: expression, purification, and enzymatic studies in a high capacity non-radioactive TR-FRET Lance assayWei-Guo Zhang
Department of Discovery Oncology, Wyeth Research, Pearl River, NY 10965, USA
Protein Expr Purif 46:414-20. 2006..Our data provide a new simplified strategy to achieve rapid production of active S6K and demonstrate utility of the Lance assay for S6K enzyme screen in searching for specific inhibitors... - 2-Arylureidophenyl-4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)triazines as highly potent and selective ATP competitive mTOR inhibitors: optimization of human microsomal stabilityJeroen C Verheijen
Chemical Sciences, Wyeth Research, Pearl River, NY 10965, USA
Bioorg Med Chem Lett 20:2648-53. 2010..Combination of tetrahydropyran substitution with an N-Me-piperazinophenylureido group led to 27, that selectively suppressed mTOR biomarkers in vivo and possessed excellent efficacy in a murine xenograft model... - Pyranonaphthoquinone lactones: a new class of AKT selective kinase inhibitors alkylate a regulatory loop cysteineEdward J Salaski
Departments of Chemical and Screening Sciences and Oncology, Wyeth Research, 401 North Middletown Road, Pearl River, New York 10965, USA
J Med Chem 52:2181-4. 2009..Biochemical data are presented supporting a proposed bioreductive alkylation mechanism of action... - Mammalian target of rapamycin: discovery of rapamycin reveals a signaling pathway important for normal and cancer cell growthJames J Gibbons
Department of Oncology Discovery, Pfizer Inc, 401 N Middletown Rd, Pearl River, NY 10960, USA
Semin Oncol 36:S3-S17. 2009.... - Requirement of the mTOR kinase for the regulation of Maf1 phosphorylation and control of RNA polymerase III-dependent transcription in cancer cellsBoris Shor
Discovery Oncology, Wyeth Research, Pearl River, New York 10965, USA
J Biol Chem 285:15380-92. 2010..Our results highlight a new and unique mode of regulation of Pol III transcription by mTOR and suggest that normalization of Pol III activity may contribute to the therapeutic efficacy of mTOR inhibitors... - Triazines incorporating (R)-3-methylmorpholine are potent inhibitors of the mammalian target of rapamycin (mTOR) with selectivity over PI3KalphaDavid J Richard
Chemical Sciences, Wyeth Research, Pearl River, NY 10965, USA
Bioorg Med Chem Lett 20:2654-7. 2010..Such compounds also demonstrated good selectivity over the related lipid kinase PI3Kalpha. Incorporation of additional functionality at the 4-position of the arylureidophenyl ring resulted in compounds with enhanced cellular activity... - Characterization of the cloned full-length and a truncated human target of rapamycin: activity, specificity, and enzyme inhibition as studied by a high capacity assayLourdes Toral-Barza
Department of Discovery Oncology, Wyeth Research, Pearl River, NY 10965, USA
Biochem Biophys Res Commun 332:304-10. 2005..Our data indicate that TOR exhibits kinetic features of those shared by traditional serine/threonine kinases and demonstrate the feasibility for TOR enzyme screen in searching for new inhibitors... - Isolation and structure of homotemsirolimuses A, B, and CFangming Kong
Wyeth Research, 401 N Middletown Road, Pearl River, New York 10965, USA
J Nat Prod 74:547-53. 2011..The results suggested that the mTOR inhibition and antiproliferation potencies for 2a, 2b, and 2c are comparable to those of rapamycin (1) and temsirolimus (2)... - Isolation, structure determination and biological activity of 15-deoxo-7,32-O-didesmethylrapamycin from the soil actinomycete LL-D45042Edmund I Graziani
Department of Chemical and Screening Sciences, Oncology, Wyeth Research, 401 North Middletown Road, Pearl River, New York, 10965, USA
J Antibiot (Tokyo) 57:462-4. 2004 - Ammonia derived from glutaminolysis is a diffusible regulator of autophagyChristina H Eng
Center for Integrative Biology and Biotherapeutics, Pfizer, Pearl River, NY 10965, USA
Sci Signal 3:ra31. 2010..Thus, Gln metabolism not only fuels cell growth but also generates an autocrine- and paracrine-acting regulator of autophagic flux in proliferating cells... - Culicinin D, an antitumor peptaibol produced by the fungus Culicinomyces clavisporus, strain LL-12I252Haiyin He
Wyeth Research, Pearl River, New York 10965, USA
J Nat Prod 69:736-41. 2006..Studies on the 3D structure of 4 using NOE data and computer modeling revealed a dominant conformation of the right-handed helix...