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Hiroshi Miki - One of the best experts on this subject based on the ideXlab platform.
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design and synthesis of pyrrolo 3 2 d pyrimidine human Epidermal Growth Factor receptor 2 her2 Epidermal Growth Factor receptor egfr dual inhibitors exploration of novel back pocket binders
Journal of Medicinal Chemistry, 2012Co-Authors: Youichi Kawakita, Hiroshi Banno, Toshiya Tamura, Akiko Nakayama, Hiroshi Miki, Tomohiro Ohashi, Tadashi Yusa, Hidehisa Iwata, Hidenori Kamiguchi, Toshimasa TanakaAbstract:To develop novel human Epidermal Growth Factor receptor 2 (HER2)/Epidermal Growth Factor receptor (EGFR) kinase inhibitors, we explored pyrrolo[3,2-d]pyrimidine derivatives bearing bicyclic fused rings designed to fit the back pocket of the HER2/EGFR proteins. Among them, the 1,2-benzisothiazole (42m) ring was selected as a suitable back pocket binder because of its potent HER2/EGFR binding and cell Growth inhibitory (GI) activities and pseudoirreversibility (PI) profile as well as good bioavailability (BA). Ultimately, we arrived at our preclinical candidate 51m by optimization of the N-5 side chain to improve CYP inhibition and metabolic stability profiles without a loss of potency (HER2/EGFR inhibitory activity, IC50, 0.98/2.5 nM; and GI activity BT-474 cells, GI50, 2.0 nM). Reflecting the strong in vitro activities, 51m exhibited potent tumor regressive efficacy against both HER2- and EGFR-overexpressing tumor (4–1ST and CAL27) xenograft models in mice at oral doses of 50 mg/kg and 100 mg/kg.
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design and synthesis of novel human Epidermal Growth Factor receptor 2 her2 Epidermal Growth Factor receptor egfr dual inhibitors bearing a pyrrolo 3 2 d pyrimidine scaffold
Journal of Medicinal Chemistry, 2011Co-Authors: Tomoyasu Ishikawa, Masaki Seto, Hiroshi Banno, Youichi Kawakita, Mami Oorui, Takahiko Taniguchi, Yoshikazu Ohta, Toshiya Tamura, Akiko Nakayama, Hiroshi MikiAbstract:Dual inhibitors of human Epidermal Growth Factor receptor 2 (HER2) and Epidermal Growth Factor receptor (EGFR) have been investigated for breast, lung, gastric, prostate, and other cancers; one, lapatinib, is currently approved for breast cancer. To develop novel HER2/EGFR dual kinase inhibitors, we designed and synthesized pyrrolo[3,2-d]pyrimidine derivatives capable of fitting into the receptors’ ATP binding site. Among the prepared compounds, 34e showed potent HER2 and EGFR (HER1) inhibitory activities as well as tumor Growth inhibitory activity. The X-ray cocrystal structures of 34e with both HER2 and EGFR demonstrated that 34e interacts with the expected residues in their respective ATP pockets. Furthermore, reflecting its good oral bioavailability, 34e exhibited potent in vivo efficacy in HER2-overexpressing tumor xenograft models. On the basis of these findings, we report 34e (TAK-285) as a promising candidate for clinical development as a novel HER2/EGFR dual kinase inhibitor.
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design and synthesis of novel human Epidermal Growth Factor receptor 2 her2 Epidermal Growth Factor receptor egfr dual inhibitors bearing a pyrrolo 3 2 d pyrimidine scaffold
Journal of Medicinal Chemistry, 2011Co-Authors: Tomoyasu Ishikawa, Masaki Seto, Hiroshi Banno, Youichi Kawakita, Mami Oorui, Takahiko Taniguchi, Yoshikazu Ohta, Toshiya Tamura, Akiko Nakayama, Hiroshi MikiAbstract:Dual inhibitors of human Epidermal Growth Factor receptor 2 (HER2) and Epidermal Growth Factor receptor (EGFR) have been investigated for breast, lung, gastric, prostate, and other cancers; one, lapatinib, is currently approved for breast cancer. To develop novel HER2/EGFR dual kinase inhibitors, we designed and synthesized pyrrolo[3,2-d]pyrimidine derivatives capable of fitting into the receptors’ ATP binding site. Among the prepared compounds, 34e showed potent HER2 and EGFR (HER1) inhibitory activities as well as tumor Growth inhibitory activity. The X-ray cocrystal structures of 34e with both HER2 and EGFR demonstrated that 34e interacts with the expected residues in their respective ATP pockets. Furthermore, reflecting its good oral bioavailability, 34e exhibited potent in vivo efficacy in HER2-overexpressing tumor xenograft models. On the basis of these findings, we report 34e (TAK-285) as a promising candidate for clinical development as a novel HER2/EGFR dual kinase inhibitor.
Youichi Kawakita - One of the best experts on this subject based on the ideXlab platform.
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design and synthesis of pyrrolo 3 2 d pyrimidine human Epidermal Growth Factor receptor 2 her2 Epidermal Growth Factor receptor egfr dual inhibitors exploration of novel back pocket binders
Journal of Medicinal Chemistry, 2012Co-Authors: Youichi Kawakita, Hiroshi Banno, Toshiya Tamura, Akiko Nakayama, Hiroshi Miki, Tomohiro Ohashi, Tadashi Yusa, Hidehisa Iwata, Hidenori Kamiguchi, Toshimasa TanakaAbstract:To develop novel human Epidermal Growth Factor receptor 2 (HER2)/Epidermal Growth Factor receptor (EGFR) kinase inhibitors, we explored pyrrolo[3,2-d]pyrimidine derivatives bearing bicyclic fused rings designed to fit the back pocket of the HER2/EGFR proteins. Among them, the 1,2-benzisothiazole (42m) ring was selected as a suitable back pocket binder because of its potent HER2/EGFR binding and cell Growth inhibitory (GI) activities and pseudoirreversibility (PI) profile as well as good bioavailability (BA). Ultimately, we arrived at our preclinical candidate 51m by optimization of the N-5 side chain to improve CYP inhibition and metabolic stability profiles without a loss of potency (HER2/EGFR inhibitory activity, IC50, 0.98/2.5 nM; and GI activity BT-474 cells, GI50, 2.0 nM). Reflecting the strong in vitro activities, 51m exhibited potent tumor regressive efficacy against both HER2- and EGFR-overexpressing tumor (4–1ST and CAL27) xenograft models in mice at oral doses of 50 mg/kg and 100 mg/kg.
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design and synthesis of novel human Epidermal Growth Factor receptor 2 her2 Epidermal Growth Factor receptor egfr dual inhibitors bearing a pyrrolo 3 2 d pyrimidine scaffold
Journal of Medicinal Chemistry, 2011Co-Authors: Tomoyasu Ishikawa, Masaki Seto, Hiroshi Banno, Youichi Kawakita, Mami Oorui, Takahiko Taniguchi, Yoshikazu Ohta, Toshiya Tamura, Akiko Nakayama, Hiroshi MikiAbstract:Dual inhibitors of human Epidermal Growth Factor receptor 2 (HER2) and Epidermal Growth Factor receptor (EGFR) have been investigated for breast, lung, gastric, prostate, and other cancers; one, lapatinib, is currently approved for breast cancer. To develop novel HER2/EGFR dual kinase inhibitors, we designed and synthesized pyrrolo[3,2-d]pyrimidine derivatives capable of fitting into the receptors’ ATP binding site. Among the prepared compounds, 34e showed potent HER2 and EGFR (HER1) inhibitory activities as well as tumor Growth inhibitory activity. The X-ray cocrystal structures of 34e with both HER2 and EGFR demonstrated that 34e interacts with the expected residues in their respective ATP pockets. Furthermore, reflecting its good oral bioavailability, 34e exhibited potent in vivo efficacy in HER2-overexpressing tumor xenograft models. On the basis of these findings, we report 34e (TAK-285) as a promising candidate for clinical development as a novel HER2/EGFR dual kinase inhibitor.
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design and synthesis of novel human Epidermal Growth Factor receptor 2 her2 Epidermal Growth Factor receptor egfr dual inhibitors bearing a pyrrolo 3 2 d pyrimidine scaffold
Journal of Medicinal Chemistry, 2011Co-Authors: Tomoyasu Ishikawa, Masaki Seto, Hiroshi Banno, Youichi Kawakita, Mami Oorui, Takahiko Taniguchi, Yoshikazu Ohta, Toshiya Tamura, Akiko Nakayama, Hiroshi MikiAbstract:Dual inhibitors of human Epidermal Growth Factor receptor 2 (HER2) and Epidermal Growth Factor receptor (EGFR) have been investigated for breast, lung, gastric, prostate, and other cancers; one, lapatinib, is currently approved for breast cancer. To develop novel HER2/EGFR dual kinase inhibitors, we designed and synthesized pyrrolo[3,2-d]pyrimidine derivatives capable of fitting into the receptors’ ATP binding site. Among the prepared compounds, 34e showed potent HER2 and EGFR (HER1) inhibitory activities as well as tumor Growth inhibitory activity. The X-ray cocrystal structures of 34e with both HER2 and EGFR demonstrated that 34e interacts with the expected residues in their respective ATP pockets. Furthermore, reflecting its good oral bioavailability, 34e exhibited potent in vivo efficacy in HER2-overexpressing tumor xenograft models. On the basis of these findings, we report 34e (TAK-285) as a promising candidate for clinical development as a novel HER2/EGFR dual kinase inhibitor.
Ronald Deblanc - One of the best experts on this subject based on the ideXlab platform.
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6 substituted 4 3 bromophenylamino quinazolines as putative irreversible inhibitors of the Epidermal Growth Factor receptor egfr and human Epidermal Growth Factor receptor her 2 tyrosine kinases with enhanced antitumor activity
Journal of Medicinal Chemistry, 2001Co-Authors: Hweiru Tsou, Nellie Mamuya, Bernard D Johnson, Marvin F Reich, Brian C Gruber, Fei Ye, Ramaswamy Nilakantan, Ru Shen, Carolyn Discafani, Ronald DeblancAbstract:A series of new 6-substituted-4-(3-bromophenylamino)quinazoline derivatives that may function as irreversible inhibitors of Epidermal Growth Factor receptor (EGFR) and human Epidermal Growth Factor receptor (HER-2) tyrosine kinases have been prepared. These inhibitors have, at the C-6 position, butynamide, crotonamide, and methacrylamide Michael acceptors bearing water-solublilizing substituents. These compounds were prepared by acylation of 6-amino-4-(3-bromophenylamino)quinazoline with unsaturated acid chlorides or mixed anhydrides. We show that attaching a basic functional group onto the Michael acceptor results in greater reactivity, due to intramolecular catalysis of the Michael addition and/or an inductive effect of the protonated basic group. This, along with improved water solubility, results in compounds with enhanced biological properties. We present molecular modeling and experimental evidence that these inhibitors interact covalently with the target enzymes. One compound, 16a, was shown to hav...
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6 substituted 4 3 bromophenylamino quinazolines as putative irreversible inhibitors of the Epidermal Growth Factor receptor egfr and human Epidermal Growth Factor receptor her 2 tyrosine kinases with enhanced antitumor activity
Journal of Medicinal Chemistry, 2001Co-Authors: Hweiru Tsou, Nellie Mamuya, Bernard D Johnson, Marvin F Reich, Brian C Gruber, Ramaswamy Nilakantan, Ru Shen, Carolyn Discafani, Ronald Deblanc, Rachel DavisAbstract:A series of new 6-substituted-4-(3-bromophenylamino)quinazoline derivatives that may function as irreversible inhibitors of Epidermal Growth Factor receptor (EGFR) and human Epidermal Growth Factor receptor (HER-2) tyrosine kinases have been prepared. These inhibitors have, at the C-6 position, butynamide, crotonamide, and methacrylamide Michael acceptors bearing water-solublilizing substituents. These compounds were prepared by acylation of 6-amino-4-(3-bromophenylamino)quinazoline with unsaturated acid chlorides or mixed anhydrides. We show that attaching a basic functional group onto the Michael acceptor results in greater reactivity, due to intramolecular catalysis of the Michael addition and/or an inductive effect of the protonated basic group. This, along with improved water solubility, results in compounds with enhanced biological properties. We present molecular modeling and experimental evidence that these inhibitors interact covalently with the target enzymes. One compound, 16a, was shown to have excellent oral activity in a human epidermoid carcinoma (A431) xenograft model in nude mice.
Akiko Nakayama - One of the best experts on this subject based on the ideXlab platform.
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design and synthesis of pyrrolo 3 2 d pyrimidine human Epidermal Growth Factor receptor 2 her2 Epidermal Growth Factor receptor egfr dual inhibitors exploration of novel back pocket binders
Journal of Medicinal Chemistry, 2012Co-Authors: Youichi Kawakita, Hiroshi Banno, Toshiya Tamura, Akiko Nakayama, Hiroshi Miki, Tomohiro Ohashi, Tadashi Yusa, Hidehisa Iwata, Hidenori Kamiguchi, Toshimasa TanakaAbstract:To develop novel human Epidermal Growth Factor receptor 2 (HER2)/Epidermal Growth Factor receptor (EGFR) kinase inhibitors, we explored pyrrolo[3,2-d]pyrimidine derivatives bearing bicyclic fused rings designed to fit the back pocket of the HER2/EGFR proteins. Among them, the 1,2-benzisothiazole (42m) ring was selected as a suitable back pocket binder because of its potent HER2/EGFR binding and cell Growth inhibitory (GI) activities and pseudoirreversibility (PI) profile as well as good bioavailability (BA). Ultimately, we arrived at our preclinical candidate 51m by optimization of the N-5 side chain to improve CYP inhibition and metabolic stability profiles without a loss of potency (HER2/EGFR inhibitory activity, IC50, 0.98/2.5 nM; and GI activity BT-474 cells, GI50, 2.0 nM). Reflecting the strong in vitro activities, 51m exhibited potent tumor regressive efficacy against both HER2- and EGFR-overexpressing tumor (4–1ST and CAL27) xenograft models in mice at oral doses of 50 mg/kg and 100 mg/kg.
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design and synthesis of novel human Epidermal Growth Factor receptor 2 her2 Epidermal Growth Factor receptor egfr dual inhibitors bearing a pyrrolo 3 2 d pyrimidine scaffold
Journal of Medicinal Chemistry, 2011Co-Authors: Tomoyasu Ishikawa, Masaki Seto, Hiroshi Banno, Youichi Kawakita, Mami Oorui, Takahiko Taniguchi, Yoshikazu Ohta, Toshiya Tamura, Akiko Nakayama, Hiroshi MikiAbstract:Dual inhibitors of human Epidermal Growth Factor receptor 2 (HER2) and Epidermal Growth Factor receptor (EGFR) have been investigated for breast, lung, gastric, prostate, and other cancers; one, lapatinib, is currently approved for breast cancer. To develop novel HER2/EGFR dual kinase inhibitors, we designed and synthesized pyrrolo[3,2-d]pyrimidine derivatives capable of fitting into the receptors’ ATP binding site. Among the prepared compounds, 34e showed potent HER2 and EGFR (HER1) inhibitory activities as well as tumor Growth inhibitory activity. The X-ray cocrystal structures of 34e with both HER2 and EGFR demonstrated that 34e interacts with the expected residues in their respective ATP pockets. Furthermore, reflecting its good oral bioavailability, 34e exhibited potent in vivo efficacy in HER2-overexpressing tumor xenograft models. On the basis of these findings, we report 34e (TAK-285) as a promising candidate for clinical development as a novel HER2/EGFR dual kinase inhibitor.
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design and synthesis of novel human Epidermal Growth Factor receptor 2 her2 Epidermal Growth Factor receptor egfr dual inhibitors bearing a pyrrolo 3 2 d pyrimidine scaffold
Journal of Medicinal Chemistry, 2011Co-Authors: Tomoyasu Ishikawa, Masaki Seto, Hiroshi Banno, Youichi Kawakita, Mami Oorui, Takahiko Taniguchi, Yoshikazu Ohta, Toshiya Tamura, Akiko Nakayama, Hiroshi MikiAbstract:Dual inhibitors of human Epidermal Growth Factor receptor 2 (HER2) and Epidermal Growth Factor receptor (EGFR) have been investigated for breast, lung, gastric, prostate, and other cancers; one, lapatinib, is currently approved for breast cancer. To develop novel HER2/EGFR dual kinase inhibitors, we designed and synthesized pyrrolo[3,2-d]pyrimidine derivatives capable of fitting into the receptors’ ATP binding site. Among the prepared compounds, 34e showed potent HER2 and EGFR (HER1) inhibitory activities as well as tumor Growth inhibitory activity. The X-ray cocrystal structures of 34e with both HER2 and EGFR demonstrated that 34e interacts with the expected residues in their respective ATP pockets. Furthermore, reflecting its good oral bioavailability, 34e exhibited potent in vivo efficacy in HER2-overexpressing tumor xenograft models. On the basis of these findings, we report 34e (TAK-285) as a promising candidate for clinical development as a novel HER2/EGFR dual kinase inhibitor.
Toshiya Tamura - One of the best experts on this subject based on the ideXlab platform.
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design and synthesis of pyrrolo 3 2 d pyrimidine human Epidermal Growth Factor receptor 2 her2 Epidermal Growth Factor receptor egfr dual inhibitors exploration of novel back pocket binders
Journal of Medicinal Chemistry, 2012Co-Authors: Youichi Kawakita, Hiroshi Banno, Toshiya Tamura, Akiko Nakayama, Hiroshi Miki, Tomohiro Ohashi, Tadashi Yusa, Hidehisa Iwata, Hidenori Kamiguchi, Toshimasa TanakaAbstract:To develop novel human Epidermal Growth Factor receptor 2 (HER2)/Epidermal Growth Factor receptor (EGFR) kinase inhibitors, we explored pyrrolo[3,2-d]pyrimidine derivatives bearing bicyclic fused rings designed to fit the back pocket of the HER2/EGFR proteins. Among them, the 1,2-benzisothiazole (42m) ring was selected as a suitable back pocket binder because of its potent HER2/EGFR binding and cell Growth inhibitory (GI) activities and pseudoirreversibility (PI) profile as well as good bioavailability (BA). Ultimately, we arrived at our preclinical candidate 51m by optimization of the N-5 side chain to improve CYP inhibition and metabolic stability profiles without a loss of potency (HER2/EGFR inhibitory activity, IC50, 0.98/2.5 nM; and GI activity BT-474 cells, GI50, 2.0 nM). Reflecting the strong in vitro activities, 51m exhibited potent tumor regressive efficacy against both HER2- and EGFR-overexpressing tumor (4–1ST and CAL27) xenograft models in mice at oral doses of 50 mg/kg and 100 mg/kg.
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design and synthesis of novel human Epidermal Growth Factor receptor 2 her2 Epidermal Growth Factor receptor egfr dual inhibitors bearing a pyrrolo 3 2 d pyrimidine scaffold
Journal of Medicinal Chemistry, 2011Co-Authors: Tomoyasu Ishikawa, Masaki Seto, Hiroshi Banno, Youichi Kawakita, Mami Oorui, Takahiko Taniguchi, Yoshikazu Ohta, Toshiya Tamura, Akiko Nakayama, Hiroshi MikiAbstract:Dual inhibitors of human Epidermal Growth Factor receptor 2 (HER2) and Epidermal Growth Factor receptor (EGFR) have been investigated for breast, lung, gastric, prostate, and other cancers; one, lapatinib, is currently approved for breast cancer. To develop novel HER2/EGFR dual kinase inhibitors, we designed and synthesized pyrrolo[3,2-d]pyrimidine derivatives capable of fitting into the receptors’ ATP binding site. Among the prepared compounds, 34e showed potent HER2 and EGFR (HER1) inhibitory activities as well as tumor Growth inhibitory activity. The X-ray cocrystal structures of 34e with both HER2 and EGFR demonstrated that 34e interacts with the expected residues in their respective ATP pockets. Furthermore, reflecting its good oral bioavailability, 34e exhibited potent in vivo efficacy in HER2-overexpressing tumor xenograft models. On the basis of these findings, we report 34e (TAK-285) as a promising candidate for clinical development as a novel HER2/EGFR dual kinase inhibitor.
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design and synthesis of novel human Epidermal Growth Factor receptor 2 her2 Epidermal Growth Factor receptor egfr dual inhibitors bearing a pyrrolo 3 2 d pyrimidine scaffold
Journal of Medicinal Chemistry, 2011Co-Authors: Tomoyasu Ishikawa, Masaki Seto, Hiroshi Banno, Youichi Kawakita, Mami Oorui, Takahiko Taniguchi, Yoshikazu Ohta, Toshiya Tamura, Akiko Nakayama, Hiroshi MikiAbstract:Dual inhibitors of human Epidermal Growth Factor receptor 2 (HER2) and Epidermal Growth Factor receptor (EGFR) have been investigated for breast, lung, gastric, prostate, and other cancers; one, lapatinib, is currently approved for breast cancer. To develop novel HER2/EGFR dual kinase inhibitors, we designed and synthesized pyrrolo[3,2-d]pyrimidine derivatives capable of fitting into the receptors’ ATP binding site. Among the prepared compounds, 34e showed potent HER2 and EGFR (HER1) inhibitory activities as well as tumor Growth inhibitory activity. The X-ray cocrystal structures of 34e with both HER2 and EGFR demonstrated that 34e interacts with the expected residues in their respective ATP pockets. Furthermore, reflecting its good oral bioavailability, 34e exhibited potent in vivo efficacy in HER2-overexpressing tumor xenograft models. On the basis of these findings, we report 34e (TAK-285) as a promising candidate for clinical development as a novel HER2/EGFR dual kinase inhibitor.