Semiramis Ayral-Kaloustian

Summary

Affiliation: Wyeth Research
Country: USA

Publications

  1. doi Cevipabulin (TTI-237): preclinical and clinical results for a novel antimicrotubule agent
    S Ayral-Kaloustian
    Chemical Sciences, Discovery Medicinal Chemistry, Wyeth Research, Pearl River, NY 10965, USA
    Methods Find Exp Clin Pharmacol 31:443-7. 2009
  2. doi Hybrid inhibitors of phosphatidylinositol 3-kinase (PI3K) and the mammalian target of rapamycin (mTOR): design, synthesis, and superior antitumor activity of novel wortmannin-rapamycin conjugates
    Semiramis Ayral-Kaloustian
    Discovery Medicinal Chemistry, Wyeth Research, 401 North Middletown Road, Pearl River, New York 10965, USA
    J Med Chem 53:452-9. 2010
  3. doi ATP-competitive inhibitors of the mammalian target of rapamycin: design and synthesis of highly potent and selective pyrazolopyrimidines
    Arie Zask
    Wyeth Research, 401 N Middletown Road, Pearl River, NY 10965, USA
    J Med Chem 52:5013-6. 2009
  4. doi Synthesis and SAR of novel 4-morpholinopyrrolopyrimidine derivatives as potent phosphatidylinositol 3-kinase inhibitors
    Zecheng Chen
    Chemical Sciences, Wyeth Research, 401 N Middletown Road, Pearl River, New York 10965, USA
    J Med Chem 53:3169-82. 2010
  5. ncbi PWT-458, a novel pegylated-17-hydroxywortmannin, inhibits phosphatidylinositol 3-kinase signaling and suppresses growth of solid tumors
    Ker Yu
    Department of Oncology Research, Wyeth Research, Pearl River, NY, USA
    Cancer Biol Ther 4:538-45. 2005
  6. doi 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 inhibitor
    Aranapakam M Venkatesan
    Chemical Sciences, Wyeth Research, 401 N Middletown Road, Pearl River, New York 10965, USA
    J Med Chem 53:2636-45. 2010
  7. doi Pyrazolopyrimidines as highly potent and selective, ATP-competitive inhibitors of the mammalian target of rapamycin (mTOR): optimization of the 1-substituent
    Kevin J Curran
    Chemical Sciences, Wyeth Research, 401 N Middletown Rd, Pearl River, NY 10965, USA
    Bioorg Med Chem Lett 20:1440-4. 2010
  8. doi 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
  9. doi TTI-237: a novel microtubule-active compound with in vivo antitumor activity
    Carl F Beyer
    Discovery Oncology, Wyeth Research, Pearl River, New York, NY 10965, USA
    Cancer Res 68:2292-300. 2008
  10. ncbi HTI-286, a synthetic analogue of the tripeptide hemiasterlin, is a potent antimicrotubule agent that circumvents P-glycoprotein-mediated resistance in vitro and in vivo
    Frank Loganzo
    Oncology Research, Wyeth Research, Pearl River, New York 10965, USA
    Cancer Res 63:1838-45. 2003

Detail Information

Publications43

  1. doi Cevipabulin (TTI-237): preclinical and clinical results for a novel antimicrotubule agent
    S Ayral-Kaloustian
    Chemical Sciences, Discovery Medicinal Chemistry, Wyeth Research, Pearl River, NY 10965, USA
    Methods Find Exp Clin Pharmacol 31:443-7. 2009
    ..Furthermore, cevipabulin is stable and water-soluble, and can be administered i.v. or p.o. in saline. It can be synthesized in bulk quantities efficiently. Based on these properties, cevipabulin was selected for clinical development...
  2. doi Hybrid inhibitors of phosphatidylinositol 3-kinase (PI3K) and the mammalian target of rapamycin (mTOR): design, synthesis, and superior antitumor activity of novel wortmannin-rapamycin conjugates
    Semiramis 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...
  3. doi ATP-competitive inhibitors of the mammalian target of rapamycin: design and synthesis of highly potent and selective pyrazolopyrimidines
    Arie 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...
  4. doi Synthesis and SAR of novel 4-morpholinopyrrolopyrimidine derivatives as potent phosphatidylinositol 3-kinase inhibitors
    Zecheng 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...
  5. ncbi PWT-458, a novel pegylated-17-hydroxywortmannin, inhibits phosphatidylinositol 3-kinase signaling and suppresses growth of solid tumors
    Ker 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...
  6. doi 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 inhibitor
    Aranapakam 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...
  7. doi Pyrazolopyrimidines as highly potent and selective, ATP-competitive inhibitors of the mammalian target of rapamycin (mTOR): optimization of the 1-substituent
    Kevin J Curran
    Chemical Sciences, Wyeth Research, 401 N Middletown Rd, Pearl River, NY 10965, USA
    Bioorg Med Chem Lett 20:1440-4. 2010
    ....
  8. doi 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...
  9. doi TTI-237: a novel microtubule-active compound with in vivo antitumor activity
    Carl F Beyer
    Discovery Oncology, Wyeth Research, Pearl River, New York, NY 10965, USA
    Cancer Res 68:2292-300. 2008
    ..v. or p.o. Thus, TTI-237 has a set of properties that distinguish it from other classes of microtubule-active compounds...
  10. ncbi HTI-286, a synthetic analogue of the tripeptide hemiasterlin, is a potent antimicrotubule agent that circumvents P-glycoprotein-mediated resistance in vitro and in vivo
    Frank Loganzo
    Oncology Research, Wyeth Research, Pearl River, New York 10965, USA
    Cancer Res 63:1838-45. 2003
    ....
  11. doi 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 substituent
    Jeroen 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)...
  12. doi Beyond rapalog therapy: preclinical pharmacology and antitumor activity of WYE-125132, an ATP-competitive and specific inhibitor of mTORC1 and mTORC2
    Ker Yu
    Discovery Oncology and Discovery Medicinal Chemistry, Wyeth Research, Pearl River, New York 10965, USA
    Cancer Res 70:621-31. 2010
    ....
  13. doi Lead optimization of N-3-substituted 7-morpholinotriazolopyrimidines as dual phosphoinositide 3-kinase/mammalian target of rapamycin inhibitors: discovery of PKI-402
    Christoph 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...
  14. ncbi 5-ureidobenzofuranone indoles as potent and efficacious inhibitors of PI3 kinase-alpha and mTOR for the treatment of breast cancer
    Nan 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...
  15. doi 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...
  16. doi Novel imidazolopyrimidines as dual PI3-Kinase/mTOR inhibitors
    Aranapakam 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...
  17. ncbi Synthesis and activity of novel analogs of hemiasterlin as inhibitors of tubulin polymerization: modification of the A segment
    Ayako Yamashita
    Chemical and Screening Sciences and Oncology Research, Wyeth Research, Pearl River, NY 10965, USA
    Bioorg Med Chem Lett 14:5317-22. 2004
    ....
  18. ncbi Cells resistant to HTI-286 do not overexpress P-glycoprotein but have reduced drug accumulation and a point mutation in alpha-tubulin
    Frank Loganzo
    Oncology Research, Wyeth Research, 401 North Middletown Road, 200 4709, Pearl River, NY 10965, USA
    Mol Cancer Ther 3:1319-27. 2004
    ..These data suggest that HTI-286 resistance may be partially mediated by mutation of alpha-tubulin and by an ATP-binding cassette drug pump distinct from P-glycoprotein, ABCG2, MRP1, or MRP3...
  19. doi Antitumor efficacy of PKI-587, a highly potent dual PI3K/mTOR kinase inhibitor
    Robert Mallon
    Department of Oncology, Discovery Medicinal Chemistry, and Drug Safety and Metabolism, Wyeth Research now Pfizer, Pearl River, New York 10965, USA
    Clin Cancer Res 17:3193-203. 2011
    ..The aim of this study was to show preclinical efficacy and clinical development potential of PKI-587, a dual phosphoinositide 3-kinase (PI3K)/mTOR inhibitor...
  20. doi Antitumor efficacy profile of PKI-402, a dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor
    Robert Mallon
    Wyeth Research, 401 North Middletown Road, Pearl River, NY 10965 USA
    Mol Cancer Ther 9:976-84. 2010
    ..We are testing whether dual PI3K/mTOR inhibitors can durably suppress p-Akt, induce cleaved PARP, and cause tumor regression in a diverse set of human tumor xenograft models. Mol Cancer Ther; 9(4); 976-84. (c)2010 AACR...
  21. doi 4-(Phenylaminomethylene)isoquinoline-1,3(2H,4H)-diones as potent and selective inhibitors of the cyclin-dependent kinase 4 (CDK4)
    Hwei Ru Tsou
    Wyeth Research, 401 N Middletown Road, Pearl River, NY 10965, USA
    J Med Chem 51:3507-25. 2008
    ..We present here SAR data and a CDK4 mimic model that explains the binding, potency, and selectivity of our CDK4 selective inhibitors...
  22. doi Design and synthesis of novel diaminoquinazolines with in vivo efficacy for beta-catenin/T-cell transcriptional factor 4 pathway inhibition
    Christoph M Dehnhardt
    Discovery Medicinal Chemistry, Wyeth Research, Pearl River, New York 10965, USA
    J Med Chem 53:897-910. 2010
    ..Subsequently, 9 was tested for efficacy in a beta-catenin/RKE-mouse xenograft, where it led to more then 50% decrease in tumor volume...
  23. doi PKI-179: an orally efficacious dual phosphatidylinositol-3-kinase (PI3K)/mammalian target of rapamycin (mTOR) inhibitor
    Aranapakam 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...
  24. doi Morpholine derivatives greatly enhance the selectivity of mammalian target of rapamycin (mTOR) inhibitors
    Arie 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...
  25. doi Identification of 2-oxatriazines as highly potent pan-PI3K/mTOR dual inhibitors
    Christoph 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...
  26. ncbi Synthesis and SAR of [1,2,4]triazolo[1,5-a]pyrimidines, a class of anticancer agents with a unique mechanism of tubulin inhibition
    Nan Zhang
    Chemical and Screening Sciences, Wyeth Research, Pearl River, New York 10965, USA
    J Med Chem 50:319-27. 2007
    ..Lead compounds were shown to inhibit tumor growth in several nude mouse xenograft models, with high potency and efficacy, when dosed either orally or intravenously...
  27. ncbi 2-cyanoaminopyrimidines as a class of antitumor agents that promote tubulin polymerization
    Nan Zhang
    Discovery Medicinal Chemistry, Chemical and Screening Sciences, Wyeth Research, Pearl River, NY 10965, USA
    Bioorg Med Chem Lett 17:3003-5. 2007
    ..These findings strongly suggest that this series of 2-cyanoaminopyrimidines binds at the same site and in the same binding mode as TTI-237. Further modifications of the 2-cyanoamino group are underway...
  28. doi Stereoselective synthesis of an active metabolite of the potent PI3 kinase inhibitor PKI-179
    Zecheng Chen
    Chemical Sciences, Wyeth Research, 401 North Middletown Road, Pearl River, New York 10956, USA
    J Org Chem 75:1643-51. 2010
    ..Compound 2 was found to be enantiomerically pure and identical to the enantiomer 28. The absolute stereochemistry of the enantiomer 28 was determined by Mosher's method, thus establishing the stereochemistry of the active metabolite 2...
  29. doi Synthesis and SAR of 6-chloro-4-fluoroalkylamino-2-heteroaryl-5-(substituted)phenylpyrimidines as anti-cancer agents
    Nan Zhang
    Chemical and Screening Sciences, Wyeth Research, 401 North Middletown Road, Pearl River, New York 10965, USA
    Bioorg Med Chem 17:111-8. 2009
    ..Compound 21 (PTI-868) showed tumor growth inhibition in several nude mouse xenograft models, and was selected to advance to preclinical development...
  30. ncbi Synthesis and biological activity of analogues of the antimicrotubule agent N,beta,beta-trimethyl-L-phenylalanyl-N(1)-[(1S,2E)-3-carboxy-1-isopropylbut-2-enyl]- N(1),3-dimethyl-L-valinamide (HTI-286)
    Arie Zask
    Chemical and Screening Sciences, and Oncology Research, Wyeth Research, 401 North Middletown Road, Pearl River, New York 10965, USA
    J Med Chem 47:4774-86. 2004
    ..Groups tolerant of modification, leading to novel analogues, are reported. Potent analogues identified through in vivo studies in tumor xenograft models include one superior analogue, HTI-042...
  31. ncbi D-piece modifications of the hemiasterlin analog HTI-286 produce potent tubulin inhibitors
    Arie Zask
    Wyeth Research, Chemical and Screening Sciences, 401 North Middletown Road, Pearl River, NY 10965, USA
    Bioorg Med Chem Lett 14:4353-8. 2004
    ..Synthetic modifications of the carboxylic acid could be carried out selectively using a wide range of synthetic reagents. Proline analog 3 was found to be effective in a human xenograft model in athymic mice...
  32. doi 2-Aryl-4,5,6,7-tetrahydro-1,3-benzothiazol-7-ols as a class of antitumor agents selectively active in securin(-/-) cells
    Nan Zhang
    Discovery Medicinal Chemistry, Chemical Sciences, Wyeth Research, Pearl River, NY 10965, USA
    Bioorg Med Chem Lett 20:3903-5. 2010
    ..Compound 19 showed the highest potency against MCF-7 and MDA-MB-361 lines and was selected for further evaluation...
  33. doi Absolute configurations of tubulin inhibitors taltobulin (HTI-286) and HTI-042 characterized by X-ray diffraction analysis and NMR studies
    Chuansheng Niu
    Wyeth Research, Pearl River, NY 10965, USA
    Bioorg Med Chem Lett 20:1535-8. 2010
    ..Single crystal X-ray diffraction analysis further confirmed the absolute configuration of these two compounds, which carry the (S,S,S)-configuration necessary for biological activity...
  34. ncbi Pegylated wortmannin and 17-hydroxywortmannin conjugates as phosphoinositide 3-kinase inhibitors active in human tumor xenograft models
    Tianmin 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...
  35. ncbi Benzodiazepine inhibitors of the MMPs and TACE. Part 2
    Jeremy I Levin
    Wyeth Research, 401N Middletown Road, Pearl River, NY 10965, USA
    Bioorg Med Chem Lett 14:4147-51. 2004
    ..A series of benzodiazepine MMP/TACE inhibitors bearing polar moieties has been synthesized in an effort to optimize inhibitory activity against LPS-stimulated TNF production in human monocytes and oral activity in a murine LPS model...
  36. ncbi Tubulin inhibitors. Synthesis and biological activity of HTI-286 analogs with B-segment heterosubstituents
    Chuan Niu
    Chemical and Screening Sciences, Discovery Medicinal Chemistry, Wyeth Research, 401 N Middletown Road, Pearl River, NY 10965, USA
    Bioorg Med Chem Lett 14:4329-32. 2004
    ..These analogs were more potent than paclitaxel against P-glycoprotein expressing KB-8-5 and KB-V1 cell lines. Several analogs showed strong inhibition of tubulin polymerization...
  37. doi 2,4-Diamino-quinazolines as inhibitors of beta-catenin/Tcf-4 pathway: Potential treatment for colorectal cancer
    Zecheng Chen
    Wyeth Research, Chemical Sciences, 401 N Middletown Road, Pearl River, NY 10965, USA
    Bioorg Med Chem Lett 19:4980-3. 2009
    ..Compound such as 16k exhibited good cellular potency, solubility, metabolic stability and oral bioavailability...
  38. ncbi Two photoaffinity analogues of the tripeptide, hemiasterlin, exclusively label alpha-tubulin
    Maria Nunes
    Oncology Research, Chemical and Screening Sciences, Radiosynthesis Group, and Bioorganic Enzymology, Wyeth Research, 401 North Middletown Road, Pearl River, New York 10965, USA
    Biochemistry 44:6844-57. 2005
    ..In addition, we speculate that antimitotic peptides mimic the interaction of stathmin with tubulin...
  39. doi Discovery of 4-(benzylaminomethylene)isoquinoline-1,3-(2H,4H)-diones and 4-[(pyridylmethyl)aminomethylene]isoquinoline-1,3-(2H,4H)-diones as potent and selective inhibitors of the cyclin-dependent kinase 4
    Hwei Ru Tsou
    Chemical and Screening Sciences, and Oncology Research, Wyeth Research, 401 N Middletown Road, Pearl River, New York 10965, USA
    J Med Chem 52:2289-310. 2009
    ..We present here the synthesis, SAR data, metabolic stability data, and a CDK4 mimic model that explains the binding, potency, and selectivity of our CDK4 selective inhibitors...
  40. ncbi The microtubule-active antitumor compound TTI-237 has both paclitaxel-like and vincristine-like properties
    Carl F Beyer
    Department of Discovery Oncology, Wyeth Research, Pearl River, NY 10965, USA
    Cancer Chemother Pharmacol 64:681-9. 2009
    ....
  41. ncbi Biochemical, cellular, and in vivo activity of novel ATP-competitive and selective inhibitors of the mammalian target of rapamycin
    Ker Yu
    Discovery Oncology, Wyeth Research, Pearl River, New York 10965, USA
    Cancer Res 69:6232-40. 2009
    ....
  42. ncbi Synthesis and SAR of diazepine and thiazepine TACE and MMP inhibitors
    Arie Zask
    Wyeth Research, 401 N Middletown Road, Pearl River, NY 10965, USA
    Bioorg Med Chem Lett 15:1641-5. 2005
    ..Oral activity in the mouse LPS model of TNF-alpha release was seen. Efficacy in the mouse collagen induced arthritis model was achieved with diazepine 20...
  43. ncbi Protein farnesyltransferase inhibitors
    Semiramis Ayral-Kaloustian
    Wyeth Research, Pearl River, NY 10965 1299, USA
    Curr Med Chem 9:1003-32. 2002
    ..This article will review the progress that has been reported with FTase inhibitors in drug discovery and in the clinic...