Affiliation: Wyeth Research
- HTI-286, a synthetic analogue of the tripeptide hemiasterlin, is a potent antimicrotubule agent that circumvents P-glycoprotein-mediated resistance in vitro and in vivoFrank Loganzo
Oncology Research, Wyeth Research, Pearl River, New York 10965, USA
Cancer Res 63:1838-45. 2003....
- Cells resistant to HTI-286 do not overexpress P-glycoprotein but have reduced drug accumulation and a point mutation in alpha-tubulinFrank 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...
- Paclitaxel-resistant cells have a mutation in the paclitaxel-binding region of beta-tubulin (Asp26Glu) and less stable microtubulesMalathi Hari
Discovery Oncology, Wyeth, 401 North Middletown Road, Room 4709, Building 200, Pearl River, NY 10965, USA
Mol Cancer Ther 5:270-8. 2006..These results suggest that a mutation in tubulin might affect microtubule stability as well as drug binding and contribute to the observed resistance profile...
- Synthesis and activity of novel analogs of hemiasterlin as inhibitors of tubulin polymerization: modification of the A segmentAyako Yamashita
Chemical and Screening Sciences and Oncology Research, Wyeth Research, Pearl River, NY 10965, USA
Bioorg Med Chem Lett 14:5317-22. 2004....
- Two photoaffinity analogues of the tripeptide, hemiasterlin, exclusively label alpha-tubulinMaria 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...
- Dual irreversible kinase inhibitors: quinazoline-based inhibitors incorporating two independent reactive centers with each targeting different cysteine residues in the kinase domains of EGFR and VEGFR-2Allan Wissner
Chemical and Screening Sciences and Oncology Research, Wyeth Research, 401 N Middletown Road, Pearl River, NY 10965, USA
Bioorg Med Chem 15:3635-48. 2007..The relative dependence of the IC(50) values on the concentration of ATP used in the assays suggests that these compounds appear to function as irreversible inhibitors of each kinase...
- 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...
- 2-(Quinazolin-4-ylamino)-[1,4]benzoquinones as covalent-binding, irreversible inhibitors of the kinase domain of vascular endothelial growth factor receptor-2Allan Wissner
Chemical and Screening Sciences and Oncology Research, Wyeth Research, 401 N Middletown Road, Pearl River, New York 10965, USA
J Med Chem 48:7560-81. 2005..Unequivocal evidence, from mass spectral studies, indicates that these inhibitors form a covalent interaction with Cys-1045. One member of this series displays antitumor activity in an in vivo model...
- Hybrids of the hemiasterlin analogue taltobulin and the dolastatins are potent antimicrotubule agentsArie Zask
Chemical and Screening Sciences and Oncology Research, Wyeth Research, 401 North Middletown Road, Pearl River, New York 10965, USA
J Am Chem Soc 127:17667-71. 2005....
- MAC-321, a novel taxane with greater efficacy than paclitaxel and docetaxel in vitro and in vivoDeepak Sampath
Wyeth Research, Department of Oncology, Pearl River, NY 10965, USA
Mol Cancer Ther 2:873-84. 2003..MAC-321 was also highly effective when given as single i.v. dose. Our findings suggest that MAC-321, which is currently under clinical evaluation, may have broad therapeutic value...
- D-piece modifications of the hemiasterlin analog HTI-286 produce potent tubulin inhibitorsArie 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...
- Biophysical characterization of the interactions of HTI-286 with tubulin heterodimer and microtubulesGirija Krishnamurthy
Biophysics Enzymology, Screening Sciences, Oncology Research, and Chemical Sciences, Wyeth Research, Pearl River, New York 10965, USA
Biochemistry 42:13484-95. 2003..In contrast to the microtubule-stabilizing effects of paclitaxel, both HTI-286 and hemiasterlin depolymerize preassembled microtubules at micromolar concentrations...
- Tubulin inhibitors. Synthesis and biological activity of HTI-286 analogs with B-segment heterosubstituentsChuan 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...
- Syntheses and EGFR kinase inhibitory activity of 6-substituted-4-anilino [1,7] and [1,8] naphthyridine-3-carbonitrilesAllan Wissner
Chemical and Screening Sciences and Oncology Research, Wyeth Research, 401N Middletown Road, Pearl River, NY 10965, USA
Bioorg Med Chem Lett 14:1411-6. 2004..Compounds having a 1,7-naphthyridine core structure can retain high potency while those with a 1,8-naphthyridine core are significantly less active. These results are consistent with molecular modeling observations...
- Targeting vascular and avascular compartments of tumors with C. novyi-NT and anti-microtubule agentsLong H Dang
Howard Hughes Medical Institute and Sidney Kimmel Cancer Center, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA
Cancer Biol Ther 3:326-37. 2004..novyi-NT spores could germinate. A single intravenous injection of C. novyi-NT plus selected anti-microtubule agents was able to cause regressions of several human tumor xenografts in nude mice in the absence of excessive toxicity...
- Tumor cells resistant to a microtubule-depolymerizing hemiasterlin analogue, HTI-286, have mutations in alpha- or beta-tubulin and increased microtubule stabilityMarianne S Poruchynsky
Cancer Therapeutics Branch, The NCI Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892, USA
Biochemistry 43:13944-54. 2004..Unlike reports of mutations resulting in reduced drug affinity, the experimental data and location of mutations are consistent with resistance to HTI-286 mediated by microtubule-stabilizing mutations in beta- or alpha-tubulin...