Discovery of mobocertinib, a potent, oral inhibitor of
In the treatment of non–small cell lung cancer (NSCLC), patients harboring exon 20 insertion mutations in the epidermal growth factor receptor (EGFR) gene (EGFR) have few effective therapies because this subset of mutants is generally resistant to most currently approved EGFR inhibitors. This report...
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| Autor*in: |
Huang, Wei-Sheng [verfasserIn] Li, Feng [verfasserIn] Gong, Yongjin [verfasserIn] Zhang, Yun [verfasserIn] Youngsaye, Willmen [verfasserIn] Xu, Yongjin [verfasserIn] Zhu, Xiaotian [verfasserIn] Greenfield, Matthew T. [verfasserIn] Kohlmann, Anna [verfasserIn] Taslimi, Paul M. [verfasserIn] Toms, Angela [verfasserIn] Zech, Stephan G. [verfasserIn] Zhou, Tianjun [verfasserIn] Das, Biplab [verfasserIn] Jang, Hyun G. [verfasserIn] Tugnait, Meera [verfasserIn] Ye, Yihua E. [verfasserIn] Gonzalvez, Francois [verfasserIn] Baker, Theresa E. [verfasserIn] Nadworny, Sara [verfasserIn] Ning, Yaoyu [verfasserIn] Wardwell, Scott D. [verfasserIn] Zhang, Sen [verfasserIn] Gould, Alexandra E. [verfasserIn] Hu, Yongbo [verfasserIn] Lane, Weston [verfasserIn] Skene, Robert J. [verfasserIn] Zou, Hua [verfasserIn] Clackson, Tim [verfasserIn] Narasimhan, Narayana I. [verfasserIn] Rivera, Victor M. [verfasserIn] Dalgarno, David C. [verfasserIn] Shakespeare, William C. [verfasserIn] |
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| Format: |
E-Artikel |
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| Sprache: |
Englisch |
| Erschienen: |
2022 |
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| Schlagwörter: |
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| Übergeordnetes Werk: |
Enthalten in: Bioorganic & medicinal chemistry letters - Amsterdam [u.a.] : Elsevier Science, 1991, 80 |
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| Übergeordnetes Werk: |
volume:80 |
| DOI / URN: |
10.1016/j.bmcl.2022.129084 |
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| Katalog-ID: |
ELV009110135 |
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| 245 | 1 | 0 | |a Discovery of mobocertinib, a potent, oral inhibitor of |
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| 520 | |a In the treatment of non–small cell lung cancer (NSCLC), patients harboring exon 20 insertion mutations in the epidermal growth factor receptor (EGFR) gene (EGFR) have few effective therapies because this subset of mutants is generally resistant to most currently approved EGFR inhibitors. This report describes the structure-guided design of a novel series of potent, irreversible inhibitors of EGFR exon 20 insertion mutations, including the V769_D770insASV and D770_N771insSVD mutants. Extensive structure–activity relationship (SAR) studies led to the discovery of mobocertinib (compound 21c), which inhibited growth of Ba/F3 cells expressing the ASV insertion with a half-maximal inhibitory concentration of 11 nM and with selectivity over wild-type EGFR. Daily oral administration of mobocertinib induced tumor regression in a Ba/F3 ASV xenograft mouse model at well-tolerated doses. Mobocertinib was approved in September 2021 for the treatment of adult patients with advanced NSCLC with EGFR exon 20 insertion mutations with progression on or after platinum-based chemotherapy. | ||
| 650 | 4 | |a Exon 20 insertion | |
| 650 | 4 | |a Non–small cell lung cancer | |
| 650 | 4 | |a Mobocertinib | |
| 650 | 4 | |a Drug resistance | |
| 700 | 1 | |a Li, Feng |e verfasserin |4 aut | |
| 700 | 1 | |a Gong, Yongjin |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Yun |e verfasserin |4 aut | |
| 700 | 1 | |a Youngsaye, Willmen |e verfasserin |4 aut | |
| 700 | 1 | |a Xu, Yongjin |e verfasserin |4 aut | |
| 700 | 1 | |a Zhu, Xiaotian |e verfasserin |4 aut | |
| 700 | 1 | |a Greenfield, Matthew T. |e verfasserin |4 aut | |
| 700 | 1 | |a Kohlmann, Anna |e verfasserin |4 aut | |
| 700 | 1 | |a Taslimi, Paul M. |e verfasserin |4 aut | |
| 700 | 1 | |a Toms, Angela |e verfasserin |4 aut | |
| 700 | 1 | |a Zech, Stephan G. |e verfasserin |4 aut | |
| 700 | 1 | |a Zhou, Tianjun |e verfasserin |4 aut | |
| 700 | 1 | |a Das, Biplab |e verfasserin |4 aut | |
| 700 | 1 | |a Jang, Hyun G. |e verfasserin |4 aut | |
| 700 | 1 | |a Tugnait, Meera |e verfasserin |4 aut | |
| 700 | 1 | |a Ye, Yihua E. |e verfasserin |4 aut | |
| 700 | 1 | |a Gonzalvez, Francois |e verfasserin |4 aut | |
| 700 | 1 | |a Baker, Theresa E. |e verfasserin |4 aut | |
| 700 | 1 | |a Nadworny, Sara |e verfasserin |4 aut | |
| 700 | 1 | |a Ning, Yaoyu |e verfasserin |4 aut | |
| 700 | 1 | |a Wardwell, Scott D. |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Sen |e verfasserin |4 aut | |
| 700 | 1 | |a Gould, Alexandra E. |e verfasserin |4 aut | |
| 700 | 1 | |a Hu, Yongbo |e verfasserin |4 aut | |
| 700 | 1 | |a Lane, Weston |e verfasserin |4 aut | |
| 700 | 1 | |a Skene, Robert J. |e verfasserin |4 aut | |
| 700 | 1 | |a Zou, Hua |e verfasserin |4 aut | |
| 700 | 1 | |a Clackson, Tim |e verfasserin |4 aut | |
| 700 | 1 | |a Narasimhan, Narayana I. |e verfasserin |4 aut | |
| 700 | 1 | |a Rivera, Victor M. |e verfasserin |4 aut | |
| 700 | 1 | |a Dalgarno, David C. |e verfasserin |4 aut | |
| 700 | 1 | |a Shakespeare, William C. |e verfasserin |4 aut | |
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10.1016/j.bmcl.2022.129084 doi (DE-627)ELV009110135 (ELSEVIER)S0960-894X(22)00560-1 DE-627 ger DE-627 rda eng 540 610 DE-600 15,3 ssgn PHARM DE-84 fid 35.70 bkl 44.33 bkl 44.42 bkl Huang, Wei-Sheng verfasserin aut Discovery of mobocertinib, a potent, oral inhibitor of 2022 nicht spezifiziert zzz rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier In the treatment of non–small cell lung cancer (NSCLC), patients harboring exon 20 insertion mutations in the epidermal growth factor receptor (EGFR) gene (EGFR) have few effective therapies because this subset of mutants is generally resistant to most currently approved EGFR inhibitors. This report describes the structure-guided design of a novel series of potent, irreversible inhibitors of EGFR exon 20 insertion mutations, including the V769_D770insASV and D770_N771insSVD mutants. Extensive structure–activity relationship (SAR) studies led to the discovery of mobocertinib (compound 21c), which inhibited growth of Ba/F3 cells expressing the ASV insertion with a half-maximal inhibitory concentration of 11 nM and with selectivity over wild-type EGFR. Daily oral administration of mobocertinib induced tumor regression in a Ba/F3 ASV xenograft mouse model at well-tolerated doses. Mobocertinib was approved in September 2021 for the treatment of adult patients with advanced NSCLC with EGFR exon 20 insertion mutations with progression on or after platinum-based chemotherapy. Exon 20 insertion Non–small cell lung cancer Mobocertinib Drug resistance Li, Feng verfasserin aut Gong, Yongjin verfasserin aut Zhang, Yun verfasserin aut Youngsaye, Willmen verfasserin aut Xu, Yongjin verfasserin aut Zhu, Xiaotian verfasserin aut Greenfield, Matthew T. verfasserin aut Kohlmann, Anna verfasserin aut Taslimi, Paul M. verfasserin aut Toms, Angela verfasserin aut Zech, Stephan G. verfasserin aut Zhou, Tianjun verfasserin aut Das, Biplab verfasserin aut Jang, Hyun G. verfasserin aut Tugnait, Meera verfasserin aut Ye, Yihua E. verfasserin aut Gonzalvez, Francois verfasserin aut Baker, Theresa E. verfasserin aut Nadworny, Sara verfasserin aut Ning, Yaoyu verfasserin aut Wardwell, Scott D. verfasserin aut Zhang, Sen verfasserin aut Gould, Alexandra E. verfasserin aut Hu, Yongbo verfasserin aut Lane, Weston verfasserin aut Skene, Robert J. verfasserin aut Zou, Hua verfasserin aut Clackson, Tim verfasserin aut Narasimhan, Narayana I. verfasserin aut Rivera, Victor M. verfasserin aut Dalgarno, David C. verfasserin aut Shakespeare, William C. verfasserin aut Enthalten in Bioorganic & medicinal chemistry letters Amsterdam [u.a.] : Elsevier Science, 1991 80 Online-Ressource (DE-627)306717522 (DE-600)1501505-1 (DE-576)110916573 1464-3405 nnns volume:80 GBV_USEFLAG_U SYSFLAG_U GBV_ELV FID-PHARM SSG-OLC-PHA SSG-OPC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_150 GBV_ILN_151 GBV_ILN_224 GBV_ILN_370 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2056 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2336 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4313 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4393 35.70 Biochemie: Allgemeines 44.33 Physiologische Chemie 44.42 Pharmazeutische Chemie AR 80 |
| spelling |
10.1016/j.bmcl.2022.129084 doi (DE-627)ELV009110135 (ELSEVIER)S0960-894X(22)00560-1 DE-627 ger DE-627 rda eng 540 610 DE-600 15,3 ssgn PHARM DE-84 fid 35.70 bkl 44.33 bkl 44.42 bkl Huang, Wei-Sheng verfasserin aut Discovery of mobocertinib, a potent, oral inhibitor of 2022 nicht spezifiziert zzz rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier In the treatment of non–small cell lung cancer (NSCLC), patients harboring exon 20 insertion mutations in the epidermal growth factor receptor (EGFR) gene (EGFR) have few effective therapies because this subset of mutants is generally resistant to most currently approved EGFR inhibitors. This report describes the structure-guided design of a novel series of potent, irreversible inhibitors of EGFR exon 20 insertion mutations, including the V769_D770insASV and D770_N771insSVD mutants. Extensive structure–activity relationship (SAR) studies led to the discovery of mobocertinib (compound 21c), which inhibited growth of Ba/F3 cells expressing the ASV insertion with a half-maximal inhibitory concentration of 11 nM and with selectivity over wild-type EGFR. Daily oral administration of mobocertinib induced tumor regression in a Ba/F3 ASV xenograft mouse model at well-tolerated doses. Mobocertinib was approved in September 2021 for the treatment of adult patients with advanced NSCLC with EGFR exon 20 insertion mutations with progression on or after platinum-based chemotherapy. Exon 20 insertion Non–small cell lung cancer Mobocertinib Drug resistance Li, Feng verfasserin aut Gong, Yongjin verfasserin aut Zhang, Yun verfasserin aut Youngsaye, Willmen verfasserin aut Xu, Yongjin verfasserin aut Zhu, Xiaotian verfasserin aut Greenfield, Matthew T. verfasserin aut Kohlmann, Anna verfasserin aut Taslimi, Paul M. verfasserin aut Toms, Angela verfasserin aut Zech, Stephan G. verfasserin aut Zhou, Tianjun verfasserin aut Das, Biplab verfasserin aut Jang, Hyun G. verfasserin aut Tugnait, Meera verfasserin aut Ye, Yihua E. verfasserin aut Gonzalvez, Francois verfasserin aut Baker, Theresa E. verfasserin aut Nadworny, Sara verfasserin aut Ning, Yaoyu verfasserin aut Wardwell, Scott D. verfasserin aut Zhang, Sen verfasserin aut Gould, Alexandra E. verfasserin aut Hu, Yongbo verfasserin aut Lane, Weston verfasserin aut Skene, Robert J. verfasserin aut Zou, Hua verfasserin aut Clackson, Tim verfasserin aut Narasimhan, Narayana I. verfasserin aut Rivera, Victor M. verfasserin aut Dalgarno, David C. verfasserin aut Shakespeare, William C. verfasserin aut Enthalten in Bioorganic & medicinal chemistry letters Amsterdam [u.a.] : Elsevier Science, 1991 80 Online-Ressource (DE-627)306717522 (DE-600)1501505-1 (DE-576)110916573 1464-3405 nnns volume:80 GBV_USEFLAG_U SYSFLAG_U GBV_ELV FID-PHARM SSG-OLC-PHA SSG-OPC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_150 GBV_ILN_151 GBV_ILN_224 GBV_ILN_370 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2056 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2336 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4313 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4393 35.70 Biochemie: Allgemeines 44.33 Physiologische Chemie 44.42 Pharmazeutische Chemie AR 80 |
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10.1016/j.bmcl.2022.129084 doi (DE-627)ELV009110135 (ELSEVIER)S0960-894X(22)00560-1 DE-627 ger DE-627 rda eng 540 610 DE-600 15,3 ssgn PHARM DE-84 fid 35.70 bkl 44.33 bkl 44.42 bkl Huang, Wei-Sheng verfasserin aut Discovery of mobocertinib, a potent, oral inhibitor of 2022 nicht spezifiziert zzz rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier In the treatment of non–small cell lung cancer (NSCLC), patients harboring exon 20 insertion mutations in the epidermal growth factor receptor (EGFR) gene (EGFR) have few effective therapies because this subset of mutants is generally resistant to most currently approved EGFR inhibitors. This report describes the structure-guided design of a novel series of potent, irreversible inhibitors of EGFR exon 20 insertion mutations, including the V769_D770insASV and D770_N771insSVD mutants. Extensive structure–activity relationship (SAR) studies led to the discovery of mobocertinib (compound 21c), which inhibited growth of Ba/F3 cells expressing the ASV insertion with a half-maximal inhibitory concentration of 11 nM and with selectivity over wild-type EGFR. Daily oral administration of mobocertinib induced tumor regression in a Ba/F3 ASV xenograft mouse model at well-tolerated doses. Mobocertinib was approved in September 2021 for the treatment of adult patients with advanced NSCLC with EGFR exon 20 insertion mutations with progression on or after platinum-based chemotherapy. Exon 20 insertion Non–small cell lung cancer Mobocertinib Drug resistance Li, Feng verfasserin aut Gong, Yongjin verfasserin aut Zhang, Yun verfasserin aut Youngsaye, Willmen verfasserin aut Xu, Yongjin verfasserin aut Zhu, Xiaotian verfasserin aut Greenfield, Matthew T. verfasserin aut Kohlmann, Anna verfasserin aut Taslimi, Paul M. verfasserin aut Toms, Angela verfasserin aut Zech, Stephan G. verfasserin aut Zhou, Tianjun verfasserin aut Das, Biplab verfasserin aut Jang, Hyun G. verfasserin aut Tugnait, Meera verfasserin aut Ye, Yihua E. verfasserin aut Gonzalvez, Francois verfasserin aut Baker, Theresa E. verfasserin aut Nadworny, Sara verfasserin aut Ning, Yaoyu verfasserin aut Wardwell, Scott D. verfasserin aut Zhang, Sen verfasserin aut Gould, Alexandra E. verfasserin aut Hu, Yongbo verfasserin aut Lane, Weston verfasserin aut Skene, Robert J. verfasserin aut Zou, Hua verfasserin aut Clackson, Tim verfasserin aut Narasimhan, Narayana I. verfasserin aut Rivera, Victor M. verfasserin aut Dalgarno, David C. verfasserin aut Shakespeare, William C. verfasserin aut Enthalten in Bioorganic & medicinal chemistry letters Amsterdam [u.a.] : Elsevier Science, 1991 80 Online-Ressource (DE-627)306717522 (DE-600)1501505-1 (DE-576)110916573 1464-3405 nnns volume:80 GBV_USEFLAG_U SYSFLAG_U GBV_ELV FID-PHARM SSG-OLC-PHA SSG-OPC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_150 GBV_ILN_151 GBV_ILN_224 GBV_ILN_370 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2056 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2336 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4313 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4393 35.70 Biochemie: Allgemeines 44.33 Physiologische Chemie 44.42 Pharmazeutische Chemie AR 80 |
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10.1016/j.bmcl.2022.129084 doi (DE-627)ELV009110135 (ELSEVIER)S0960-894X(22)00560-1 DE-627 ger DE-627 rda eng 540 610 DE-600 15,3 ssgn PHARM DE-84 fid 35.70 bkl 44.33 bkl 44.42 bkl Huang, Wei-Sheng verfasserin aut Discovery of mobocertinib, a potent, oral inhibitor of 2022 nicht spezifiziert zzz rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier In the treatment of non–small cell lung cancer (NSCLC), patients harboring exon 20 insertion mutations in the epidermal growth factor receptor (EGFR) gene (EGFR) have few effective therapies because this subset of mutants is generally resistant to most currently approved EGFR inhibitors. This report describes the structure-guided design of a novel series of potent, irreversible inhibitors of EGFR exon 20 insertion mutations, including the V769_D770insASV and D770_N771insSVD mutants. Extensive structure–activity relationship (SAR) studies led to the discovery of mobocertinib (compound 21c), which inhibited growth of Ba/F3 cells expressing the ASV insertion with a half-maximal inhibitory concentration of 11 nM and with selectivity over wild-type EGFR. Daily oral administration of mobocertinib induced tumor regression in a Ba/F3 ASV xenograft mouse model at well-tolerated doses. Mobocertinib was approved in September 2021 for the treatment of adult patients with advanced NSCLC with EGFR exon 20 insertion mutations with progression on or after platinum-based chemotherapy. Exon 20 insertion Non–small cell lung cancer Mobocertinib Drug resistance Li, Feng verfasserin aut Gong, Yongjin verfasserin aut Zhang, Yun verfasserin aut Youngsaye, Willmen verfasserin aut Xu, Yongjin verfasserin aut Zhu, Xiaotian verfasserin aut Greenfield, Matthew T. verfasserin aut Kohlmann, Anna verfasserin aut Taslimi, Paul M. verfasserin aut Toms, Angela verfasserin aut Zech, Stephan G. verfasserin aut Zhou, Tianjun verfasserin aut Das, Biplab verfasserin aut Jang, Hyun G. verfasserin aut Tugnait, Meera verfasserin aut Ye, Yihua E. verfasserin aut Gonzalvez, Francois verfasserin aut Baker, Theresa E. verfasserin aut Nadworny, Sara verfasserin aut Ning, Yaoyu verfasserin aut Wardwell, Scott D. verfasserin aut Zhang, Sen verfasserin aut Gould, Alexandra E. verfasserin aut Hu, Yongbo verfasserin aut Lane, Weston verfasserin aut Skene, Robert J. verfasserin aut Zou, Hua verfasserin aut Clackson, Tim verfasserin aut Narasimhan, Narayana I. verfasserin aut Rivera, Victor M. verfasserin aut Dalgarno, David C. verfasserin aut Shakespeare, William C. verfasserin aut Enthalten in Bioorganic & medicinal chemistry letters Amsterdam [u.a.] : Elsevier Science, 1991 80 Online-Ressource (DE-627)306717522 (DE-600)1501505-1 (DE-576)110916573 1464-3405 nnns volume:80 GBV_USEFLAG_U SYSFLAG_U GBV_ELV FID-PHARM SSG-OLC-PHA SSG-OPC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_150 GBV_ILN_151 GBV_ILN_224 GBV_ILN_370 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2056 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2336 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4313 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4393 35.70 Biochemie: Allgemeines 44.33 Physiologische Chemie 44.42 Pharmazeutische Chemie AR 80 |
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10.1016/j.bmcl.2022.129084 doi (DE-627)ELV009110135 (ELSEVIER)S0960-894X(22)00560-1 DE-627 ger DE-627 rda eng 540 610 DE-600 15,3 ssgn PHARM DE-84 fid 35.70 bkl 44.33 bkl 44.42 bkl Huang, Wei-Sheng verfasserin aut Discovery of mobocertinib, a potent, oral inhibitor of 2022 nicht spezifiziert zzz rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier In the treatment of non–small cell lung cancer (NSCLC), patients harboring exon 20 insertion mutations in the epidermal growth factor receptor (EGFR) gene (EGFR) have few effective therapies because this subset of mutants is generally resistant to most currently approved EGFR inhibitors. This report describes the structure-guided design of a novel series of potent, irreversible inhibitors of EGFR exon 20 insertion mutations, including the V769_D770insASV and D770_N771insSVD mutants. Extensive structure–activity relationship (SAR) studies led to the discovery of mobocertinib (compound 21c), which inhibited growth of Ba/F3 cells expressing the ASV insertion with a half-maximal inhibitory concentration of 11 nM and with selectivity over wild-type EGFR. Daily oral administration of mobocertinib induced tumor regression in a Ba/F3 ASV xenograft mouse model at well-tolerated doses. Mobocertinib was approved in September 2021 for the treatment of adult patients with advanced NSCLC with EGFR exon 20 insertion mutations with progression on or after platinum-based chemotherapy. Exon 20 insertion Non–small cell lung cancer Mobocertinib Drug resistance Li, Feng verfasserin aut Gong, Yongjin verfasserin aut Zhang, Yun verfasserin aut Youngsaye, Willmen verfasserin aut Xu, Yongjin verfasserin aut Zhu, Xiaotian verfasserin aut Greenfield, Matthew T. verfasserin aut Kohlmann, Anna verfasserin aut Taslimi, Paul M. verfasserin aut Toms, Angela verfasserin aut Zech, Stephan G. verfasserin aut Zhou, Tianjun verfasserin aut Das, Biplab verfasserin aut Jang, Hyun G. verfasserin aut Tugnait, Meera verfasserin aut Ye, Yihua E. verfasserin aut Gonzalvez, Francois verfasserin aut Baker, Theresa E. verfasserin aut Nadworny, Sara verfasserin aut Ning, Yaoyu verfasserin aut Wardwell, Scott D. verfasserin aut Zhang, Sen verfasserin aut Gould, Alexandra E. verfasserin aut Hu, Yongbo verfasserin aut Lane, Weston verfasserin aut Skene, Robert J. verfasserin aut Zou, Hua verfasserin aut Clackson, Tim verfasserin aut Narasimhan, Narayana I. verfasserin aut Rivera, Victor M. verfasserin aut Dalgarno, David C. verfasserin aut Shakespeare, William C. verfasserin aut Enthalten in Bioorganic & medicinal chemistry letters Amsterdam [u.a.] : Elsevier Science, 1991 80 Online-Ressource (DE-627)306717522 (DE-600)1501505-1 (DE-576)110916573 1464-3405 nnns volume:80 GBV_USEFLAG_U SYSFLAG_U GBV_ELV FID-PHARM SSG-OLC-PHA SSG-OPC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_150 GBV_ILN_151 GBV_ILN_224 GBV_ILN_370 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2056 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2336 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4313 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4393 35.70 Biochemie: Allgemeines 44.33 Physiologische Chemie 44.42 Pharmazeutische Chemie AR 80 |
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Huang, Wei-Sheng @@aut@@ Li, Feng @@aut@@ Gong, Yongjin @@aut@@ Zhang, Yun @@aut@@ Youngsaye, Willmen @@aut@@ Xu, Yongjin @@aut@@ Zhu, Xiaotian @@aut@@ Greenfield, Matthew T. @@aut@@ Kohlmann, Anna @@aut@@ Taslimi, Paul M. @@aut@@ Toms, Angela @@aut@@ Zech, Stephan G. @@aut@@ Zhou, Tianjun @@aut@@ Das, Biplab @@aut@@ Jang, Hyun G. @@aut@@ Tugnait, Meera @@aut@@ Ye, Yihua E. @@aut@@ Gonzalvez, Francois @@aut@@ Baker, Theresa E. @@aut@@ Nadworny, Sara @@aut@@ Ning, Yaoyu @@aut@@ Wardwell, Scott D. @@aut@@ Zhang, Sen @@aut@@ Gould, Alexandra E. @@aut@@ Hu, Yongbo @@aut@@ Lane, Weston @@aut@@ Skene, Robert J. @@aut@@ Zou, Hua @@aut@@ Clackson, Tim @@aut@@ Narasimhan, Narayana I. @@aut@@ Rivera, Victor M. @@aut@@ Dalgarno, David C. @@aut@@ Shakespeare, William C. @@aut@@ |
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Huang, Wei-Sheng |
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Huang, Wei-Sheng ddc 540 ssgn 15,3 fid PHARM bkl 35.70 bkl 44.33 bkl 44.42 misc Exon 20 insertion misc Non–small cell lung cancer misc Mobocertinib misc Drug resistance Discovery of mobocertinib, a potent, oral inhibitor of |
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540 610 DE-600 15,3 ssgn PHARM DE-84 fid 35.70 bkl 44.33 bkl 44.42 bkl Discovery of mobocertinib, a potent, oral inhibitor of Exon 20 insertion Non–small cell lung cancer Mobocertinib Drug resistance |
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ddc 540 ssgn 15,3 fid PHARM bkl 35.70 bkl 44.33 bkl 44.42 misc Exon 20 insertion misc Non–small cell lung cancer misc Mobocertinib misc Drug resistance |
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ddc 540 ssgn 15,3 fid PHARM bkl 35.70 bkl 44.33 bkl 44.42 misc Exon 20 insertion misc Non–small cell lung cancer misc Mobocertinib misc Drug resistance |
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Discovery of mobocertinib, a potent, oral inhibitor of |
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Discovery of mobocertinib, a potent, oral inhibitor of |
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Huang, Wei-Sheng Li, Feng Gong, Yongjin Zhang, Yun Youngsaye, Willmen Xu, Yongjin Zhu, Xiaotian Greenfield, Matthew T. Kohlmann, Anna Taslimi, Paul M. Toms, Angela Zech, Stephan G. Zhou, Tianjun Das, Biplab Jang, Hyun G. Tugnait, Meera Ye, Yihua E. Gonzalvez, Francois Baker, Theresa E. Nadworny, Sara Ning, Yaoyu Wardwell, Scott D. Zhang, Sen Gould, Alexandra E. Hu, Yongbo Lane, Weston Skene, Robert J. Zou, Hua Clackson, Tim Narasimhan, Narayana I. Rivera, Victor M. Dalgarno, David C. Shakespeare, William C. |
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Huang, Wei-Sheng |
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discovery of mobocertinib, a potent, oral inhibitor of |
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Discovery of mobocertinib, a potent, oral inhibitor of |
| abstract |
In the treatment of non–small cell lung cancer (NSCLC), patients harboring exon 20 insertion mutations in the epidermal growth factor receptor (EGFR) gene (EGFR) have few effective therapies because this subset of mutants is generally resistant to most currently approved EGFR inhibitors. This report describes the structure-guided design of a novel series of potent, irreversible inhibitors of EGFR exon 20 insertion mutations, including the V769_D770insASV and D770_N771insSVD mutants. Extensive structure–activity relationship (SAR) studies led to the discovery of mobocertinib (compound 21c), which inhibited growth of Ba/F3 cells expressing the ASV insertion with a half-maximal inhibitory concentration of 11 nM and with selectivity over wild-type EGFR. Daily oral administration of mobocertinib induced tumor regression in a Ba/F3 ASV xenograft mouse model at well-tolerated doses. Mobocertinib was approved in September 2021 for the treatment of adult patients with advanced NSCLC with EGFR exon 20 insertion mutations with progression on or after platinum-based chemotherapy. |
| abstractGer |
In the treatment of non–small cell lung cancer (NSCLC), patients harboring exon 20 insertion mutations in the epidermal growth factor receptor (EGFR) gene (EGFR) have few effective therapies because this subset of mutants is generally resistant to most currently approved EGFR inhibitors. This report describes the structure-guided design of a novel series of potent, irreversible inhibitors of EGFR exon 20 insertion mutations, including the V769_D770insASV and D770_N771insSVD mutants. Extensive structure–activity relationship (SAR) studies led to the discovery of mobocertinib (compound 21c), which inhibited growth of Ba/F3 cells expressing the ASV insertion with a half-maximal inhibitory concentration of 11 nM and with selectivity over wild-type EGFR. Daily oral administration of mobocertinib induced tumor regression in a Ba/F3 ASV xenograft mouse model at well-tolerated doses. Mobocertinib was approved in September 2021 for the treatment of adult patients with advanced NSCLC with EGFR exon 20 insertion mutations with progression on or after platinum-based chemotherapy. |
| abstract_unstemmed |
In the treatment of non–small cell lung cancer (NSCLC), patients harboring exon 20 insertion mutations in the epidermal growth factor receptor (EGFR) gene (EGFR) have few effective therapies because this subset of mutants is generally resistant to most currently approved EGFR inhibitors. This report describes the structure-guided design of a novel series of potent, irreversible inhibitors of EGFR exon 20 insertion mutations, including the V769_D770insASV and D770_N771insSVD mutants. Extensive structure–activity relationship (SAR) studies led to the discovery of mobocertinib (compound 21c), which inhibited growth of Ba/F3 cells expressing the ASV insertion with a half-maximal inhibitory concentration of 11 nM and with selectivity over wild-type EGFR. Daily oral administration of mobocertinib induced tumor regression in a Ba/F3 ASV xenograft mouse model at well-tolerated doses. Mobocertinib was approved in September 2021 for the treatment of adult patients with advanced NSCLC with EGFR exon 20 insertion mutations with progression on or after platinum-based chemotherapy. |
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| title_short |
Discovery of mobocertinib, a potent, oral inhibitor of |
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Li, Feng Gong, Yongjin Zhang, Yun Youngsaye, Willmen Xu, Yongjin Zhu, Xiaotian Greenfield, Matthew T. Kohlmann, Anna Taslimi, Paul M. Toms, Angela Zech, Stephan G. Zhou, Tianjun Das, Biplab Jang, Hyun G. Tugnait, Meera Ye, Yihua E. Gonzalvez, Francois Baker, Theresa E. Nadworny, Sara Ning, Yaoyu Wardwell, Scott D. Zhang, Sen Gould, Alexandra E. Hu, Yongbo Lane, Weston Skene, Robert J. Zou, Hua Clackson, Tim Narasimhan, Narayana I. Rivera, Victor M. Dalgarno, David C. Shakespeare, William C. |
| author2Str |
Li, Feng Gong, Yongjin Zhang, Yun Youngsaye, Willmen Xu, Yongjin Zhu, Xiaotian Greenfield, Matthew T. Kohlmann, Anna Taslimi, Paul M. Toms, Angela Zech, Stephan G. Zhou, Tianjun Das, Biplab Jang, Hyun G. Tugnait, Meera Ye, Yihua E. Gonzalvez, Francois Baker, Theresa E. Nadworny, Sara Ning, Yaoyu Wardwell, Scott D. Zhang, Sen Gould, Alexandra E. Hu, Yongbo Lane, Weston Skene, Robert J. Zou, Hua Clackson, Tim Narasimhan, Narayana I. Rivera, Victor M. Dalgarno, David C. Shakespeare, William C. |
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306717522 |
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c |
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| doi_str |
10.1016/j.bmcl.2022.129084 |
| up_date |
2024-07-06T22:01:43.400Z |
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| score |
7.4014044 |