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Masahiko Hayakawa,
Ken-Ichi Kawaguchi,
Hiroyuki Kaizawa,
Tomonobu Koizumi,
Takahide Ohishi, Mayumi Yamano,
Minoru Okada,
Mitsuaki Ohta,
Shin-Ichi Tsukamoto,
Florence I Raynaud,
Peter Parker,
Paul Workman,
Michael D Waterfield
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ABSTRACT: We have previously reported the imidazo[1,2-a]pyridine derivative 4 as a novel p110alpha inhibitor; however, although 4 is a potent inhibitor of p110alpha enzymatic activity and tumor cell proliferation in vitro, it is unstable in solution and ineffective in vivo. To increase stability the pyrazole of 4 was replaced with a hydrazone and a moderately potent p110alpha inhibitor 7a was obtained. Subsequent optimization of 7a afforded exceptionally potent p110alpha inhibitors, including 8c and 8h, with IC(50) values of 0.30 nM and 0.26 nM, respectively; to the best of our knowledge, these compounds are the most potent PI3K p110alpha inhibitors reported to date. Compound 8c was also stable in solution and exhibited significant anti-tumor effectiveness in vivo.
Bioorganic & Medicinal Chemistry 10/2007; 15(17):5837-44. · 2.92 Impact Factor
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Masahiko Hayakawa,
Hiroyuki Kaizawa,
Hiroyuki Moritomo,
Tomonobu Koizumi,
Takahide Ohishi, Mayumi Yamano,
Minoru Okada,
Mitsuaki Ohta,
Shin-ichi Tsukamoto,
Florence I Raynaud,
Paul Workman,
Michael D Waterfield,
Peter Parker
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ABSTRACT: 4-Morpholin-4-ylpyrido[3',2':4,5]thieno[3,2-d]pyrimidine 2a was discovered in our chemical library as a novel p110alpha inhibitor with an IC(50) of 1.4 microM. By structural modification of 2a, the 2-aryl-4-morpholinopyrido[3',2':4,5]furo[3,2-d]pyrimidine derivative 10e was discovered as a p110alpha inhibitor with approximately 400-fold greater potency than 2a. Evaluation of isoform selectivity showed that 10e is a potent inhibitor of p110beta. Furthermore, 10e showed anti-proliferative activity in various cell lines, including multi-drug resistant MCF7/ADR-res cells, and was effective against HeLa human cervical tumor xenografts in nude mice.
Bioorganic & Medicinal Chemistry Letters 06/2007; 17(9):2438-42. · 2.55 Impact Factor
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Masahiko Hayakawa,
Hiroyuki Kaizawa,
Ken-Ichi Kawaguchi,
Noriko Ishikawa,
Tomonobu Koizumi,
Takahide Ohishi, Mayumi Yamano,
Minoru Okada,
Mitsuaki Ohta,
Shin-Ichi Tsukamoto,
Florence I Raynaud,
Michael D Waterfield,
Peter Parker,
Paul Workman
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ABSTRACT: 3-{1-[(4-Fluorophenyl)sulfonyl]-1H-pyrazol-3-yl}-2-methylimidazo[1,2-a]pyridine, 2a, was discovered in our chemical library as a novel p110alpha inhibitor with an IC(50) of 0.67microM, through screening in a scintillation proximity assay. Optimization of the substituents of 2a increased the p110alpha inhibitory activity by more than 300-fold (2g: IC(50)=0.0018microM). Further structural modification of 2g afforded thiazole derivative 12, which has potent p110alpha inhibitory activity (IC(50) of 0.0028microM) and is highly selective for p110alpha over other PI3K isoforms. Compound 12 also inhibited serum-induced cell proliferation of A375 and HeLa cells in vitro with IC(50) values of 0.14microM and 0.21microM, respectively, and suppressed tumor growth by 37% in a mouse HeLa xenograft model when dosed intraperitoneally at 25mg/kg. These results suggest that selective p110alpha inhibitors may have potential as cancer therapeutic agents.
Bioorganic & Medicinal Chemistry 02/2007; 15(1):403-12. · 2.92 Impact Factor
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ABSTRACT: We developed an oral administration-compatible, small molecular weight antitumor agent, YM-201627 by screening for the inhibition of the proliferation of VEGF-stimulated HUVECs. YM-201627 selectively inhibited the proliferation of various endothelial cell lines induced by VEGF, bFGF, and FBS (at IC50s of 0.0039-0.12 microM), that would not be expected to have any direct antiproliferative effect on other cell types. YM-201627 inhibited angiogenesis in vitro at a concentration of 0.01 microM. In the in vivo studies, it inhibited microvessel formation induced by human melanoma A375 cells suspended in Matrigel (86% with twice-daily doses of 30 mg/kg). Moreover, once-daily oral dosing of YM-201627 to mice bearing A375 xenografts elicited significant antitumor activity (73% with daily doses of 10 mg/kg). These results suggest that YM-201627 is a selective growth inhibitor of endothelial cells, which may be useful for treatment of solid tumors.
Cancer Letters 08/2006; 238(1):119-27. · 4.24 Impact Factor
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Nobuaki Amino,
Yukitaka Ideyama, Mayumi Yamano,
Sadao Kuromitsu,
Katsuinori Tajinda,
Kiyohiro Samizu,
Hiroyuki Hisamichi,
Akira Matsuhisa,
Kenna Shirasuna,
Masafumi Kudoh,
Masayuki Shibasaki
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ABSTRACT: The vascular endothelial growth factor receptor-2 (VEGFR2) tyrosine kinase has been implicated in the pathologic angiogenesis associated with tumor growth. YM-359445 was a (3Z)-3-quinolin-2(1H)-ylidene-1,3-dihydro-2H-indol-2-one derivative found while screening based on the inhibition of VEGFR2 tyrosine kinase. The aim of this study was to analyze the efficacy of this compound both in vitro and in vivo.
We tested the effects of YM-359445 on VEGFR2 tyrosine kinase activity, cell proliferation, and angiogenesis. The antitumor activity of YM-359445 was also tested in nude mice bearing various established tumors and compared with other VEGFR2 tyrosine kinase inhibitors (ZD6474, CP-547632, CGP79787, SU11248, and AZD2171), a cytotoxic agent (paclitaxel), and an epidermal growth factor receptor tyrosine kinase inhibitor (gefitinib).
The IC50 of YM-359445 for VEGFR2 tyrosine kinase was 0.0085 micromol/L. In human vascular endothelial cells, the compound inhibited VEGF-dependent proliferation, VEGFR2 autophosphorylation, and sprout formation at concentrations of 0.001 to 0.003 micromol/L. These concentrations had no direct cytotoxic effect on cancer cells. In mice bearing various established tumors, including paclitaxel-resistant tumors, once daily oral administration of YM-359445 at doses of 0.5 to 4 mg/kg not only inhibited tumor growth but also reduced its vasculature. YM-359445 had greater antitumor activity than other VEGFR2 tyrosine kinase inhibitors. Moreover, in human lung cancer A549 xenografts, YM-359445 markedly regressed the tumors (73%) at a dose of 4 mg/kg, whereas gefitinib caused no regression even at 100 mg/kg.
Our results show that YM-359445 is more potent than orally bioavailable VEGFR2 tyrosine kinase inhibitors, which leads to great expectations for clinical applicability.
Clinical Cancer Research 04/2006; 12(5):1630-8. · 7.74 Impact Factor
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ABSTRACT: Chemotherapy using anticancer drugs induces serious the problem of multidrug resistance (MDR) in the cancer cells. In contrast, endothelial cells so rarely acquire MDR that antiangiogenesis therapy has recently been considered as an effective means for cancer chemotherapy. We screened compounds in the chemical library to find a novel and orally active antitumor agent with vascular endothelial growth factor receptor-2 tyrosine kinase (VEGF-R2 TK) inhibition. The result was YM-231146 (IC50=0.080 microM). YM-231146 inhibited VEGF-stimulated proliferation, VEGF-R2 autophosphorylation, and vessel sprout formation of human vascular endothelial cells at concentrations between 0.15-0.30 microM. However, YM-231146 did not inhibit cancer cell proliferation at these concentrations (IC50>5 microM). In the in vivo studies, once-daily oral dosing of YM-231146 to human cancer xenografts elicited antitumor activity at doses of 3-100 mg/kg. Moreover, YM-231146 completely inhibited tumor growth of paclitaxel-resistant cancer cells without decreasing body weight at a dose of 100 mg/kg. These results suggest that YM-231146 is a novel orally bioavailable inhibitor of VEGF-R2 that would be useful for the treatment of multidrug resistant tumors.
Biological & Pharmaceutical Bulletin 11/2005; 28(11):2096-101. · 1.66 Impact Factor
