The Experts below are selected from a list of 65133 Experts worldwide ranked by ideXlab platform
Takao Yamori - One of the best experts on this subject based on the ideXlab platform.
-
Antitumor Activity of zstk474 a new phosphatidylinositol 3 kinase inhibitor
Journal of the National Cancer Institute, 2006Co-Authors: Shinichi Yaguchi, Ichiro Koshimizu, Yasuhisa Fukui, Hisashi Yoshimi, Toshiyuki Matsuno, Hiroaki Gouda, Shuichi Hirono, Kanami Yamazaki, Takao YamoriAbstract:Background: We previously synthesized a novel s-triazine derivative, ZSTK474 [2-(2-difluoromethylbenzimidazol-1-yl)-4,6-dimorpholino-1,3,5-triazine], that strongly inhibited the growth of tumor cells. We identified its molecular target, investigated its effects on cellular signaling pathways, and examined its Antitumor efficacy and toxicity in vivo. Methods: We used COMPARE analysis of chemosensitivity measurements from 39 human cancer cell lines and identified phosphatidylinositol 3-kinase (PI3K) as a molecular target for ZSTK474. PI3K was immunoprecipitated from A549 cell lysates, and its Activity was measured by assessing the incorporation of 32 P into phosphatidylinositol. We used the crystal structure of the PI3K-LY294002 complex to model the binding of ZSTK474 to PI3K (where LY294002 is a known PI3K inhibitor). PI3K downstream Activity was analyzed by immunoblotting. Antitumor Activity of ZSTK474 was examined against A549, PC-3, and WiDr xenografts in nude mice. Phosphorylation of Akt, a serine/threonine protein kinase and a major signaling component downstream of PI3K, was assessed in vivo by immunohistochemistry. Results: PI3K was identified as a molecular target for ZSTK474 by COMPARE analysis. We confirmed that ZSTK474 directly inhibited PI3K Activity more efficiently than the PI3K inhibitor LY294002. At concentrations of 1 μM, ZSTK474 and LY2194002 reduced PI3K Activity to 4.7% (95% confidence interval [CI] = 3.2% to 6.1%) and 44.6% (95% CI = 38.9% to 50.3%), respectively, of the untreated control level. Molecular modeling of the PI3K-ZSTK474 complex indicated that ZSTK474 could bind to the ATP-binding pocket of PI3K. ZSTK474 inhibited phosphorylation of signaling components downstream from PI3K, such as Akt and glycogen synthase kinase 3p, and mediated a decrease in cyclin Dl levels. ZSTK474 administered orally to mice had strong Antitumor Activity against human cancer xenografts without toxic effects in critical organs. Akt phosphorylation was reduced in xenograft tumors after oral administration of ZSTK474. Conclusion: ZSTK474 is a new PI3K inhibitor with strong Antitumor Activity against human cancer xenografts without toxic effects in critical organs. ZSTK474 merits further investigation as an anticancer drug.
-
Antitumor Activity of zstk474 a new phosphatidylinositol 3 kinase inhibitor
Journal of the National Cancer Institute, 2006Co-Authors: Shinichi Yaguchi, Ichiro Koshimizu, Yasuhisa Fukui, Hisashi Yoshimi, Toshiyuki Matsuno, Hiroaki Gouda, Shuichi Hirono, Kanami Yamazaki, Takao YamoriAbstract:Background We previously synthesized a novel s-triazine derivative, ZSTK474 [2-(2-difluoromethylbenzimidazol-1-yl)-4,6-dimorpholino-1,3,5-triazine], that strongly inhibited the growth of tumor cells. We identified its molecular target, investigated its effects on cellular signaling pathways, and examined its Antitumor efficacy and toxicity in vivo. Methods We used COMPARE analysis of chemosensitivity measurements from 39 human cancer cell lines and identified phosphatidylinositol 3-kinase (PI3K) as a molecular target for ZSTK474. PI3K was immunoprecipitated from A549 cell lysates, and its Activity was measured by assessing the incorporation of 32P into phosphatidylinositol. We used the crystal structure of the PI3K-LY294002 complex to model the binding of ZSTK474 to PI3K (where LY294002 is a known PI3K inhibitor). PI3K downstream Activity was analyzed by immunoblotting. Antitumor Activity of ZSTK474 was examined against A549, PC-3, and WiDr xenografts in nude mice. Phosphorylation of Akt, a serine/threonine protein kinase and a major signaling component downstream of PI3K, was assessed in vivo by immunohistochemistry. Results PI3K was identified as a molecular target for ZSTK474 by COMPARE analysis. We confirmed that ZSTK474 directly inhibited PI3K Activity more efficiently than the PI3K inhibitor LY294002. At concentrations of 1 microM, ZSTK474 and LY2194002 reduced PI3K Activity to 4.7% (95% confidence interval [CI] = 3.2% to 6.1%) and 44.6% (95% CI = 38.9% to 50.3%), respectively, of the untreated control level. Molecular modeling of the PI3K-ZSTK474 complex indicated that ZSTK474 could bind to the ATP-binding pocket of PI3K. ZSTK474 inhibited phosphorylation of signaling components downstream from PI3K, such as Akt and glycogen synthase kinase 3beta, and mediated a decrease in cyclin D1 levels. ZSTK474 administered orally to mice had strong Antitumor Activity against human cancer xenografts without toxic effects in critical organs. Akt phosphorylation was reduced in xenograft tumors after oral administration of ZSTK474. Conclusion ZSTK474 is a new PI3K inhibitor with strong Antitumor Activity against human cancer xenografts without toxic effects in critical organs. ZSTK474 merits further investigation as an anticancer drug.
Shinichi Yaguchi - One of the best experts on this subject based on the ideXlab platform.
-
Antitumor Activity of zstk474 a new phosphatidylinositol 3 kinase inhibitor
Journal of the National Cancer Institute, 2006Co-Authors: Shinichi Yaguchi, Ichiro Koshimizu, Yasuhisa Fukui, Hisashi Yoshimi, Toshiyuki Matsuno, Hiroaki Gouda, Shuichi Hirono, Kanami Yamazaki, Takao YamoriAbstract:Background: We previously synthesized a novel s-triazine derivative, ZSTK474 [2-(2-difluoromethylbenzimidazol-1-yl)-4,6-dimorpholino-1,3,5-triazine], that strongly inhibited the growth of tumor cells. We identified its molecular target, investigated its effects on cellular signaling pathways, and examined its Antitumor efficacy and toxicity in vivo. Methods: We used COMPARE analysis of chemosensitivity measurements from 39 human cancer cell lines and identified phosphatidylinositol 3-kinase (PI3K) as a molecular target for ZSTK474. PI3K was immunoprecipitated from A549 cell lysates, and its Activity was measured by assessing the incorporation of 32 P into phosphatidylinositol. We used the crystal structure of the PI3K-LY294002 complex to model the binding of ZSTK474 to PI3K (where LY294002 is a known PI3K inhibitor). PI3K downstream Activity was analyzed by immunoblotting. Antitumor Activity of ZSTK474 was examined against A549, PC-3, and WiDr xenografts in nude mice. Phosphorylation of Akt, a serine/threonine protein kinase and a major signaling component downstream of PI3K, was assessed in vivo by immunohistochemistry. Results: PI3K was identified as a molecular target for ZSTK474 by COMPARE analysis. We confirmed that ZSTK474 directly inhibited PI3K Activity more efficiently than the PI3K inhibitor LY294002. At concentrations of 1 μM, ZSTK474 and LY2194002 reduced PI3K Activity to 4.7% (95% confidence interval [CI] = 3.2% to 6.1%) and 44.6% (95% CI = 38.9% to 50.3%), respectively, of the untreated control level. Molecular modeling of the PI3K-ZSTK474 complex indicated that ZSTK474 could bind to the ATP-binding pocket of PI3K. ZSTK474 inhibited phosphorylation of signaling components downstream from PI3K, such as Akt and glycogen synthase kinase 3p, and mediated a decrease in cyclin Dl levels. ZSTK474 administered orally to mice had strong Antitumor Activity against human cancer xenografts without toxic effects in critical organs. Akt phosphorylation was reduced in xenograft tumors after oral administration of ZSTK474. Conclusion: ZSTK474 is a new PI3K inhibitor with strong Antitumor Activity against human cancer xenografts without toxic effects in critical organs. ZSTK474 merits further investigation as an anticancer drug.
-
Antitumor Activity of zstk474 a new phosphatidylinositol 3 kinase inhibitor
Journal of the National Cancer Institute, 2006Co-Authors: Shinichi Yaguchi, Ichiro Koshimizu, Yasuhisa Fukui, Hisashi Yoshimi, Toshiyuki Matsuno, Hiroaki Gouda, Shuichi Hirono, Kanami Yamazaki, Takao YamoriAbstract:Background We previously synthesized a novel s-triazine derivative, ZSTK474 [2-(2-difluoromethylbenzimidazol-1-yl)-4,6-dimorpholino-1,3,5-triazine], that strongly inhibited the growth of tumor cells. We identified its molecular target, investigated its effects on cellular signaling pathways, and examined its Antitumor efficacy and toxicity in vivo. Methods We used COMPARE analysis of chemosensitivity measurements from 39 human cancer cell lines and identified phosphatidylinositol 3-kinase (PI3K) as a molecular target for ZSTK474. PI3K was immunoprecipitated from A549 cell lysates, and its Activity was measured by assessing the incorporation of 32P into phosphatidylinositol. We used the crystal structure of the PI3K-LY294002 complex to model the binding of ZSTK474 to PI3K (where LY294002 is a known PI3K inhibitor). PI3K downstream Activity was analyzed by immunoblotting. Antitumor Activity of ZSTK474 was examined against A549, PC-3, and WiDr xenografts in nude mice. Phosphorylation of Akt, a serine/threonine protein kinase and a major signaling component downstream of PI3K, was assessed in vivo by immunohistochemistry. Results PI3K was identified as a molecular target for ZSTK474 by COMPARE analysis. We confirmed that ZSTK474 directly inhibited PI3K Activity more efficiently than the PI3K inhibitor LY294002. At concentrations of 1 microM, ZSTK474 and LY2194002 reduced PI3K Activity to 4.7% (95% confidence interval [CI] = 3.2% to 6.1%) and 44.6% (95% CI = 38.9% to 50.3%), respectively, of the untreated control level. Molecular modeling of the PI3K-ZSTK474 complex indicated that ZSTK474 could bind to the ATP-binding pocket of PI3K. ZSTK474 inhibited phosphorylation of signaling components downstream from PI3K, such as Akt and glycogen synthase kinase 3beta, and mediated a decrease in cyclin D1 levels. ZSTK474 administered orally to mice had strong Antitumor Activity against human cancer xenografts without toxic effects in critical organs. Akt phosphorylation was reduced in xenograft tumors after oral administration of ZSTK474. Conclusion ZSTK474 is a new PI3K inhibitor with strong Antitumor Activity against human cancer xenografts without toxic effects in critical organs. ZSTK474 merits further investigation as an anticancer drug.
Takuma Sasaki - One of the best experts on this subject based on the ideXlab platform.
-
Antitumor Activity of sugar modified cytosine nucleosides
Cancer Science, 2004Co-Authors: Akira Matsuda, Takuma SasakiAbstract:β β β-D-arabinofuranosylcytosine (araC), 6-mercaptopurine, fludarabine and cladribine play an important role in the treatment of leukemias, while gemcitabine, 5-fluorouracil and its prodrugs are used extensively in the treatment of many types of solid tumors. All of these compounds are metabolized similarly to endogenous nucleosides and nucleotides. Active metabolites interfere with the de novo synthesis of nucleosides and nucleotides or inhibit the DNA chain elongation after being incorporated into the DNA strand as terminators. Furthermore, nucleoside antimetabolites incorporated into the DNA strand induce strand-breaks and finally cause apoptosis. Nucleoside antimetabolites target one or more specific enzyme(s). The mode of inhibitory action on the target enzyme is not always similar even among nucleoside antimetabolites which have the same nucleoside base, such as araC and gemcitabine. Although both nucleosides are phosphorylated by deoxycytidine kinase and are also good substrates of cytidine deaminase, only gemcitabine shows Antitumor Activity against solid tumors. This suggests that differences in the pharmacological Activity of these nucleoside antimetabolites may reflect different modes of action on target molecules. The design, in vitro cytotoxicity, in vivo Antitumor Activity, metabolism and mechanism of action of sugar-modified cytosine nucleosides, such as (2′S)-2′-deoxy-2′-C-methylcytidine (SMDC), 1-(2-deoxy-2-methylene-β-D-erythro-pentofuranosyl)cytosine (DMDC), 1-(2-C-cyano-2-deoxy-1-β-D-arabino-pentofuranosyl)cytosine (CNDAC) and 1-(3-C-ethynyl-β β β β-D-ribo-pentofuranosyl)cytosine (ECyd), developed by our groups, are discussed here. (Cancer Science 2004; 95: 105–111)
-
Antitumor Activity of sugar modified cytosine nucleosides
Cancer Science, 2004Co-Authors: Akira Matsuda, Takuma SasakiAbstract:Nucleoside analogues which show antimetabolic Activity in cells have been successfully used in the treatment of various tumors. Nucleosides such as 1-beta-D-arabinofuranosylcytosine (araC), 6-mercaptopurine, fludarabine and cladribine play an important role in the treatment of leukemias, while gemcitabine, 5-fluorouracil and its prodrugs are used extensively in the treatment of many types of solid tumors. All of these compounds are metabolized similarly to endogenous nucleosides and nucleotides. Active metabolites interfere with the de novo synthesis of nucleosides and nucleotides or inhibit the DNA chain elongation after being incorporated into the DNA strand as terminators. Furthermore, nucleoside antimetabolites incorporated into the DNA strand induce strand-breaks and finally cause apoptosis. Nucleoside antimetabolites target one or more specific enzyme(s). The mode of inhibitory action on the target enzyme is not always similar even among nucleoside antimetabolites which have the same nucleoside base, such as araC and gemcitabine. Although both nucleosides are phosphorylated by deoxycytidine kinase and are also good substrates of cytidine deaminase, only gemcitabine shows Antitumor Activity against solid tumors. This suggests that differences in the pharmacological Activity of these nucleoside antimetabolites may reflect different modes of action on target molecules. The design, in vitro cytotoxicity, in vivo Antitumor Activity, metabolism and mechanism of action of sugar-modified cytosine nucleosides, such as (2'S)-2'-deoxy-2'-C-methylcytidine (SMDC), 1-(2-deoxy-2-methylene-beta-D-erythro-pentofuranosyl)cytosine (DMDC), 1-(2-C-cyano-2-deoxy-1-beta-D-arabino-pentofuranosyl)cytosine (CNDAC) and 1-(3-C-ethynyl-beta-D-ribo-pentofura-nosyl)cytosine (ECyd), developed by our groups, are discussed here.
Yasuhisa Fukui - One of the best experts on this subject based on the ideXlab platform.
-
Antitumor Activity of zstk474 a new phosphatidylinositol 3 kinase inhibitor
Journal of the National Cancer Institute, 2006Co-Authors: Shinichi Yaguchi, Ichiro Koshimizu, Yasuhisa Fukui, Hisashi Yoshimi, Toshiyuki Matsuno, Hiroaki Gouda, Shuichi Hirono, Kanami Yamazaki, Takao YamoriAbstract:Background: We previously synthesized a novel s-triazine derivative, ZSTK474 [2-(2-difluoromethylbenzimidazol-1-yl)-4,6-dimorpholino-1,3,5-triazine], that strongly inhibited the growth of tumor cells. We identified its molecular target, investigated its effects on cellular signaling pathways, and examined its Antitumor efficacy and toxicity in vivo. Methods: We used COMPARE analysis of chemosensitivity measurements from 39 human cancer cell lines and identified phosphatidylinositol 3-kinase (PI3K) as a molecular target for ZSTK474. PI3K was immunoprecipitated from A549 cell lysates, and its Activity was measured by assessing the incorporation of 32 P into phosphatidylinositol. We used the crystal structure of the PI3K-LY294002 complex to model the binding of ZSTK474 to PI3K (where LY294002 is a known PI3K inhibitor). PI3K downstream Activity was analyzed by immunoblotting. Antitumor Activity of ZSTK474 was examined against A549, PC-3, and WiDr xenografts in nude mice. Phosphorylation of Akt, a serine/threonine protein kinase and a major signaling component downstream of PI3K, was assessed in vivo by immunohistochemistry. Results: PI3K was identified as a molecular target for ZSTK474 by COMPARE analysis. We confirmed that ZSTK474 directly inhibited PI3K Activity more efficiently than the PI3K inhibitor LY294002. At concentrations of 1 μM, ZSTK474 and LY2194002 reduced PI3K Activity to 4.7% (95% confidence interval [CI] = 3.2% to 6.1%) and 44.6% (95% CI = 38.9% to 50.3%), respectively, of the untreated control level. Molecular modeling of the PI3K-ZSTK474 complex indicated that ZSTK474 could bind to the ATP-binding pocket of PI3K. ZSTK474 inhibited phosphorylation of signaling components downstream from PI3K, such as Akt and glycogen synthase kinase 3p, and mediated a decrease in cyclin Dl levels. ZSTK474 administered orally to mice had strong Antitumor Activity against human cancer xenografts without toxic effects in critical organs. Akt phosphorylation was reduced in xenograft tumors after oral administration of ZSTK474. Conclusion: ZSTK474 is a new PI3K inhibitor with strong Antitumor Activity against human cancer xenografts without toxic effects in critical organs. ZSTK474 merits further investigation as an anticancer drug.
-
Antitumor Activity of zstk474 a new phosphatidylinositol 3 kinase inhibitor
Journal of the National Cancer Institute, 2006Co-Authors: Shinichi Yaguchi, Ichiro Koshimizu, Yasuhisa Fukui, Hisashi Yoshimi, Toshiyuki Matsuno, Hiroaki Gouda, Shuichi Hirono, Kanami Yamazaki, Takao YamoriAbstract:Background We previously synthesized a novel s-triazine derivative, ZSTK474 [2-(2-difluoromethylbenzimidazol-1-yl)-4,6-dimorpholino-1,3,5-triazine], that strongly inhibited the growth of tumor cells. We identified its molecular target, investigated its effects on cellular signaling pathways, and examined its Antitumor efficacy and toxicity in vivo. Methods We used COMPARE analysis of chemosensitivity measurements from 39 human cancer cell lines and identified phosphatidylinositol 3-kinase (PI3K) as a molecular target for ZSTK474. PI3K was immunoprecipitated from A549 cell lysates, and its Activity was measured by assessing the incorporation of 32P into phosphatidylinositol. We used the crystal structure of the PI3K-LY294002 complex to model the binding of ZSTK474 to PI3K (where LY294002 is a known PI3K inhibitor). PI3K downstream Activity was analyzed by immunoblotting. Antitumor Activity of ZSTK474 was examined against A549, PC-3, and WiDr xenografts in nude mice. Phosphorylation of Akt, a serine/threonine protein kinase and a major signaling component downstream of PI3K, was assessed in vivo by immunohistochemistry. Results PI3K was identified as a molecular target for ZSTK474 by COMPARE analysis. We confirmed that ZSTK474 directly inhibited PI3K Activity more efficiently than the PI3K inhibitor LY294002. At concentrations of 1 microM, ZSTK474 and LY2194002 reduced PI3K Activity to 4.7% (95% confidence interval [CI] = 3.2% to 6.1%) and 44.6% (95% CI = 38.9% to 50.3%), respectively, of the untreated control level. Molecular modeling of the PI3K-ZSTK474 complex indicated that ZSTK474 could bind to the ATP-binding pocket of PI3K. ZSTK474 inhibited phosphorylation of signaling components downstream from PI3K, such as Akt and glycogen synthase kinase 3beta, and mediated a decrease in cyclin D1 levels. ZSTK474 administered orally to mice had strong Antitumor Activity against human cancer xenografts without toxic effects in critical organs. Akt phosphorylation was reduced in xenograft tumors after oral administration of ZSTK474. Conclusion ZSTK474 is a new PI3K inhibitor with strong Antitumor Activity against human cancer xenografts without toxic effects in critical organs. ZSTK474 merits further investigation as an anticancer drug.
Hisashi Yoshimi - One of the best experts on this subject based on the ideXlab platform.
-
Antitumor Activity of zstk474 a new phosphatidylinositol 3 kinase inhibitor
Journal of the National Cancer Institute, 2006Co-Authors: Shinichi Yaguchi, Ichiro Koshimizu, Yasuhisa Fukui, Hisashi Yoshimi, Toshiyuki Matsuno, Hiroaki Gouda, Shuichi Hirono, Kanami Yamazaki, Takao YamoriAbstract:Background: We previously synthesized a novel s-triazine derivative, ZSTK474 [2-(2-difluoromethylbenzimidazol-1-yl)-4,6-dimorpholino-1,3,5-triazine], that strongly inhibited the growth of tumor cells. We identified its molecular target, investigated its effects on cellular signaling pathways, and examined its Antitumor efficacy and toxicity in vivo. Methods: We used COMPARE analysis of chemosensitivity measurements from 39 human cancer cell lines and identified phosphatidylinositol 3-kinase (PI3K) as a molecular target for ZSTK474. PI3K was immunoprecipitated from A549 cell lysates, and its Activity was measured by assessing the incorporation of 32 P into phosphatidylinositol. We used the crystal structure of the PI3K-LY294002 complex to model the binding of ZSTK474 to PI3K (where LY294002 is a known PI3K inhibitor). PI3K downstream Activity was analyzed by immunoblotting. Antitumor Activity of ZSTK474 was examined against A549, PC-3, and WiDr xenografts in nude mice. Phosphorylation of Akt, a serine/threonine protein kinase and a major signaling component downstream of PI3K, was assessed in vivo by immunohistochemistry. Results: PI3K was identified as a molecular target for ZSTK474 by COMPARE analysis. We confirmed that ZSTK474 directly inhibited PI3K Activity more efficiently than the PI3K inhibitor LY294002. At concentrations of 1 μM, ZSTK474 and LY2194002 reduced PI3K Activity to 4.7% (95% confidence interval [CI] = 3.2% to 6.1%) and 44.6% (95% CI = 38.9% to 50.3%), respectively, of the untreated control level. Molecular modeling of the PI3K-ZSTK474 complex indicated that ZSTK474 could bind to the ATP-binding pocket of PI3K. ZSTK474 inhibited phosphorylation of signaling components downstream from PI3K, such as Akt and glycogen synthase kinase 3p, and mediated a decrease in cyclin Dl levels. ZSTK474 administered orally to mice had strong Antitumor Activity against human cancer xenografts without toxic effects in critical organs. Akt phosphorylation was reduced in xenograft tumors after oral administration of ZSTK474. Conclusion: ZSTK474 is a new PI3K inhibitor with strong Antitumor Activity against human cancer xenografts without toxic effects in critical organs. ZSTK474 merits further investigation as an anticancer drug.
-
Antitumor Activity of zstk474 a new phosphatidylinositol 3 kinase inhibitor
Journal of the National Cancer Institute, 2006Co-Authors: Shinichi Yaguchi, Ichiro Koshimizu, Yasuhisa Fukui, Hisashi Yoshimi, Toshiyuki Matsuno, Hiroaki Gouda, Shuichi Hirono, Kanami Yamazaki, Takao YamoriAbstract:Background We previously synthesized a novel s-triazine derivative, ZSTK474 [2-(2-difluoromethylbenzimidazol-1-yl)-4,6-dimorpholino-1,3,5-triazine], that strongly inhibited the growth of tumor cells. We identified its molecular target, investigated its effects on cellular signaling pathways, and examined its Antitumor efficacy and toxicity in vivo. Methods We used COMPARE analysis of chemosensitivity measurements from 39 human cancer cell lines and identified phosphatidylinositol 3-kinase (PI3K) as a molecular target for ZSTK474. PI3K was immunoprecipitated from A549 cell lysates, and its Activity was measured by assessing the incorporation of 32P into phosphatidylinositol. We used the crystal structure of the PI3K-LY294002 complex to model the binding of ZSTK474 to PI3K (where LY294002 is a known PI3K inhibitor). PI3K downstream Activity was analyzed by immunoblotting. Antitumor Activity of ZSTK474 was examined against A549, PC-3, and WiDr xenografts in nude mice. Phosphorylation of Akt, a serine/threonine protein kinase and a major signaling component downstream of PI3K, was assessed in vivo by immunohistochemistry. Results PI3K was identified as a molecular target for ZSTK474 by COMPARE analysis. We confirmed that ZSTK474 directly inhibited PI3K Activity more efficiently than the PI3K inhibitor LY294002. At concentrations of 1 microM, ZSTK474 and LY2194002 reduced PI3K Activity to 4.7% (95% confidence interval [CI] = 3.2% to 6.1%) and 44.6% (95% CI = 38.9% to 50.3%), respectively, of the untreated control level. Molecular modeling of the PI3K-ZSTK474 complex indicated that ZSTK474 could bind to the ATP-binding pocket of PI3K. ZSTK474 inhibited phosphorylation of signaling components downstream from PI3K, such as Akt and glycogen synthase kinase 3beta, and mediated a decrease in cyclin D1 levels. ZSTK474 administered orally to mice had strong Antitumor Activity against human cancer xenografts without toxic effects in critical organs. Akt phosphorylation was reduced in xenograft tumors after oral administration of ZSTK474. Conclusion ZSTK474 is a new PI3K inhibitor with strong Antitumor Activity against human cancer xenografts without toxic effects in critical organs. ZSTK474 merits further investigation as an anticancer drug.