Novel bivalent BET inhibitor N2817 exhibits potent anticancer activity and inhibits TAF1

Bromodomain and extra-terminal domain (BET) family proteins are promising anticancer targets. Most BET inhibitors in clinical trials are monovalent. They competitively bind to one of the bromodomains (BD1 and BD2) in BET proteins and exhibit relatively weak anticancer activity, poor pharmacokinetics...
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Gespeichert in:

Autor*in:	Wu, Qian [verfasserIn] Chen, Dan-Qi [verfasserIn] Sun, Lin [verfasserIn] Huan, Xia-Juan [verfasserIn] Bao, Xu-Bin [verfasserIn] Tian, Chang-Qing [verfasserIn] Hu, Jianping [verfasserIn] Lv, Kai-Kai [verfasserIn] Wang, Ying-Qing [verfasserIn] Xiong, Bing [verfasserIn] Miao, Ze-Hong [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2021

Schlagwörter:	N2817 Bivalent BET inhibitors Monovalent BET inhibitors TAF1 Anticancer activity

Übergeordnetes Werk:	Enthalten in: Biochemical pharmacology - Amsterdam [u.a.] : Elsevier Science, 1958, 185
Übergeordnetes Werk:	volume:185

DOI / URN:	10.1016/j.bcp.2021.114435

Katalog-ID:	ELV005736463

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245	1	0	\|a Novel bivalent BET inhibitor N2817 exhibits potent anticancer activity and inhibits TAF1
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520			\|a Bromodomain and extra-terminal domain (BET) family proteins are promising anticancer targets. Most BET inhibitors in clinical trials are monovalent. They competitively bind to one of the bromodomains (BD1 and BD2) in BET proteins and exhibit relatively weak anticancer activity, poor pharmacokinetics, and low metabolic stability. Here, we evaluated the anticancer activity of a novel bivalent BET inhibitor, N2817, which consists of two molecules of the monovalent BET inhibitor 8124-053 connected by a common piperazine ring, rendering a long linker unnecessary. Compared with ABBV-075, one of the potent monovalent BET inhibitors reported to date, N2817 showed greater potency in inhibiting proliferation, arresting cell-cycle, inducing apoptosis, and suppressing the growth of tumor xenografts. Moreover, N2817 showed high metabolic stability, a relatively long half-life, and no brain penetration after oral administration. Additionally, N2817 directly bound and inhibited another BD-containing protein, TAF1 (BD2), as evidenced by a reduction in mRNA and protein levels. TAF1 inhibition contributed to the anticancer effect of N2817. Therefore, this study offers a new paradigm for designing bivalent BET inhibitors and introduces a novel potent bivalent BET inhibitor and a new anticancer mechanism.
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936	b	k	\|a 44.38 \|j Pharmakologie
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allfields	10.1016/j.bcp.2021.114435 doi (DE-627)ELV005736463 (ELSEVIER)S0006-2952(21)00031-9 DE-627 ger DE-627 rda eng 610 DE-600 PHARM DE-84 fid 44.38 bkl Wu, Qian verfasserin aut Novel bivalent BET inhibitor N2817 exhibits potent anticancer activity and inhibits TAF1 2021 nicht spezifiziert zzz rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Bromodomain and extra-terminal domain (BET) family proteins are promising anticancer targets. Most BET inhibitors in clinical trials are monovalent. They competitively bind to one of the bromodomains (BD1 and BD2) in BET proteins and exhibit relatively weak anticancer activity, poor pharmacokinetics, and low metabolic stability. Here, we evaluated the anticancer activity of a novel bivalent BET inhibitor, N2817, which consists of two molecules of the monovalent BET inhibitor 8124-053 connected by a common piperazine ring, rendering a long linker unnecessary. Compared with ABBV-075, one of the potent monovalent BET inhibitors reported to date, N2817 showed greater potency in inhibiting proliferation, arresting cell-cycle, inducing apoptosis, and suppressing the growth of tumor xenografts. Moreover, N2817 showed high metabolic stability, a relatively long half-life, and no brain penetration after oral administration. Additionally, N2817 directly bound and inhibited another BD-containing protein, TAF1 (BD2), as evidenced by a reduction in mRNA and protein levels. TAF1 inhibition contributed to the anticancer effect of N2817. Therefore, this study offers a new paradigm for designing bivalent BET inhibitors and introduces a novel potent bivalent BET inhibitor and a new anticancer mechanism. N2817 Bivalent BET inhibitors Monovalent BET inhibitors TAF1 Anticancer activity Chen, Dan-Qi verfasserin aut Sun, Lin verfasserin aut Huan, Xia-Juan verfasserin aut Bao, Xu-Bin verfasserin aut Tian, Chang-Qing verfasserin aut Hu, Jianping verfasserin aut Lv, Kai-Kai verfasserin aut Wang, Ying-Qing verfasserin aut Xiong, Bing verfasserin aut Miao, Ze-Hong verfasserin aut Enthalten in Biochemical pharmacology Amsterdam [u.a.] : Elsevier Science, 1958 185 Online-Ressource (DE-627)30631777X (DE-600)1496199-4 (DE-576)081952929 1873-2968 nnns volume:185 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_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 44.38 Pharmakologie AR 185
spelling	10.1016/j.bcp.2021.114435 doi (DE-627)ELV005736463 (ELSEVIER)S0006-2952(21)00031-9 DE-627 ger DE-627 rda eng 610 DE-600 PHARM DE-84 fid 44.38 bkl Wu, Qian verfasserin aut Novel bivalent BET inhibitor N2817 exhibits potent anticancer activity and inhibits TAF1 2021 nicht spezifiziert zzz rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Bromodomain and extra-terminal domain (BET) family proteins are promising anticancer targets. Most BET inhibitors in clinical trials are monovalent. They competitively bind to one of the bromodomains (BD1 and BD2) in BET proteins and exhibit relatively weak anticancer activity, poor pharmacokinetics, and low metabolic stability. Here, we evaluated the anticancer activity of a novel bivalent BET inhibitor, N2817, which consists of two molecules of the monovalent BET inhibitor 8124-053 connected by a common piperazine ring, rendering a long linker unnecessary. Compared with ABBV-075, one of the potent monovalent BET inhibitors reported to date, N2817 showed greater potency in inhibiting proliferation, arresting cell-cycle, inducing apoptosis, and suppressing the growth of tumor xenografts. Moreover, N2817 showed high metabolic stability, a relatively long half-life, and no brain penetration after oral administration. Additionally, N2817 directly bound and inhibited another BD-containing protein, TAF1 (BD2), as evidenced by a reduction in mRNA and protein levels. TAF1 inhibition contributed to the anticancer effect of N2817. Therefore, this study offers a new paradigm for designing bivalent BET inhibitors and introduces a novel potent bivalent BET inhibitor and a new anticancer mechanism. N2817 Bivalent BET inhibitors Monovalent BET inhibitors TAF1 Anticancer activity Chen, Dan-Qi verfasserin aut Sun, Lin verfasserin aut Huan, Xia-Juan verfasserin aut Bao, Xu-Bin verfasserin aut Tian, Chang-Qing verfasserin aut Hu, Jianping verfasserin aut Lv, Kai-Kai verfasserin aut Wang, Ying-Qing verfasserin aut Xiong, Bing verfasserin aut Miao, Ze-Hong verfasserin aut Enthalten in Biochemical pharmacology Amsterdam [u.a.] : Elsevier Science, 1958 185 Online-Ressource (DE-627)30631777X (DE-600)1496199-4 (DE-576)081952929 1873-2968 nnns volume:185 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_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 44.38 Pharmakologie AR 185
allfields_unstemmed	10.1016/j.bcp.2021.114435 doi (DE-627)ELV005736463 (ELSEVIER)S0006-2952(21)00031-9 DE-627 ger DE-627 rda eng 610 DE-600 PHARM DE-84 fid 44.38 bkl Wu, Qian verfasserin aut Novel bivalent BET inhibitor N2817 exhibits potent anticancer activity and inhibits TAF1 2021 nicht spezifiziert zzz rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Bromodomain and extra-terminal domain (BET) family proteins are promising anticancer targets. Most BET inhibitors in clinical trials are monovalent. They competitively bind to one of the bromodomains (BD1 and BD2) in BET proteins and exhibit relatively weak anticancer activity, poor pharmacokinetics, and low metabolic stability. Here, we evaluated the anticancer activity of a novel bivalent BET inhibitor, N2817, which consists of two molecules of the monovalent BET inhibitor 8124-053 connected by a common piperazine ring, rendering a long linker unnecessary. Compared with ABBV-075, one of the potent monovalent BET inhibitors reported to date, N2817 showed greater potency in inhibiting proliferation, arresting cell-cycle, inducing apoptosis, and suppressing the growth of tumor xenografts. Moreover, N2817 showed high metabolic stability, a relatively long half-life, and no brain penetration after oral administration. Additionally, N2817 directly bound and inhibited another BD-containing protein, TAF1 (BD2), as evidenced by a reduction in mRNA and protein levels. TAF1 inhibition contributed to the anticancer effect of N2817. Therefore, this study offers a new paradigm for designing bivalent BET inhibitors and introduces a novel potent bivalent BET inhibitor and a new anticancer mechanism. N2817 Bivalent BET inhibitors Monovalent BET inhibitors TAF1 Anticancer activity Chen, Dan-Qi verfasserin aut Sun, Lin verfasserin aut Huan, Xia-Juan verfasserin aut Bao, Xu-Bin verfasserin aut Tian, Chang-Qing verfasserin aut Hu, Jianping verfasserin aut Lv, Kai-Kai verfasserin aut Wang, Ying-Qing verfasserin aut Xiong, Bing verfasserin aut Miao, Ze-Hong verfasserin aut Enthalten in Biochemical pharmacology Amsterdam [u.a.] : Elsevier Science, 1958 185 Online-Ressource (DE-627)30631777X (DE-600)1496199-4 (DE-576)081952929 1873-2968 nnns volume:185 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_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 44.38 Pharmakologie AR 185
allfieldsGer	10.1016/j.bcp.2021.114435 doi (DE-627)ELV005736463 (ELSEVIER)S0006-2952(21)00031-9 DE-627 ger DE-627 rda eng 610 DE-600 PHARM DE-84 fid 44.38 bkl Wu, Qian verfasserin aut Novel bivalent BET inhibitor N2817 exhibits potent anticancer activity and inhibits TAF1 2021 nicht spezifiziert zzz rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Bromodomain and extra-terminal domain (BET) family proteins are promising anticancer targets. Most BET inhibitors in clinical trials are monovalent. They competitively bind to one of the bromodomains (BD1 and BD2) in BET proteins and exhibit relatively weak anticancer activity, poor pharmacokinetics, and low metabolic stability. Here, we evaluated the anticancer activity of a novel bivalent BET inhibitor, N2817, which consists of two molecules of the monovalent BET inhibitor 8124-053 connected by a common piperazine ring, rendering a long linker unnecessary. Compared with ABBV-075, one of the potent monovalent BET inhibitors reported to date, N2817 showed greater potency in inhibiting proliferation, arresting cell-cycle, inducing apoptosis, and suppressing the growth of tumor xenografts. Moreover, N2817 showed high metabolic stability, a relatively long half-life, and no brain penetration after oral administration. Additionally, N2817 directly bound and inhibited another BD-containing protein, TAF1 (BD2), as evidenced by a reduction in mRNA and protein levels. TAF1 inhibition contributed to the anticancer effect of N2817. Therefore, this study offers a new paradigm for designing bivalent BET inhibitors and introduces a novel potent bivalent BET inhibitor and a new anticancer mechanism. N2817 Bivalent BET inhibitors Monovalent BET inhibitors TAF1 Anticancer activity Chen, Dan-Qi verfasserin aut Sun, Lin verfasserin aut Huan, Xia-Juan verfasserin aut Bao, Xu-Bin verfasserin aut Tian, Chang-Qing verfasserin aut Hu, Jianping verfasserin aut Lv, Kai-Kai verfasserin aut Wang, Ying-Qing verfasserin aut Xiong, Bing verfasserin aut Miao, Ze-Hong verfasserin aut Enthalten in Biochemical pharmacology Amsterdam [u.a.] : Elsevier Science, 1958 185 Online-Ressource (DE-627)30631777X (DE-600)1496199-4 (DE-576)081952929 1873-2968 nnns volume:185 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_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 44.38 Pharmakologie AR 185
allfieldsSound	10.1016/j.bcp.2021.114435 doi (DE-627)ELV005736463 (ELSEVIER)S0006-2952(21)00031-9 DE-627 ger DE-627 rda eng 610 DE-600 PHARM DE-84 fid 44.38 bkl Wu, Qian verfasserin aut Novel bivalent BET inhibitor N2817 exhibits potent anticancer activity and inhibits TAF1 2021 nicht spezifiziert zzz rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Bromodomain and extra-terminal domain (BET) family proteins are promising anticancer targets. Most BET inhibitors in clinical trials are monovalent. They competitively bind to one of the bromodomains (BD1 and BD2) in BET proteins and exhibit relatively weak anticancer activity, poor pharmacokinetics, and low metabolic stability. Here, we evaluated the anticancer activity of a novel bivalent BET inhibitor, N2817, which consists of two molecules of the monovalent BET inhibitor 8124-053 connected by a common piperazine ring, rendering a long linker unnecessary. Compared with ABBV-075, one of the potent monovalent BET inhibitors reported to date, N2817 showed greater potency in inhibiting proliferation, arresting cell-cycle, inducing apoptosis, and suppressing the growth of tumor xenografts. Moreover, N2817 showed high metabolic stability, a relatively long half-life, and no brain penetration after oral administration. Additionally, N2817 directly bound and inhibited another BD-containing protein, TAF1 (BD2), as evidenced by a reduction in mRNA and protein levels. TAF1 inhibition contributed to the anticancer effect of N2817. Therefore, this study offers a new paradigm for designing bivalent BET inhibitors and introduces a novel potent bivalent BET inhibitor and a new anticancer mechanism. N2817 Bivalent BET inhibitors Monovalent BET inhibitors TAF1 Anticancer activity Chen, Dan-Qi verfasserin aut Sun, Lin verfasserin aut Huan, Xia-Juan verfasserin aut Bao, Xu-Bin verfasserin aut Tian, Chang-Qing verfasserin aut Hu, Jianping verfasserin aut Lv, Kai-Kai verfasserin aut Wang, Ying-Qing verfasserin aut Xiong, Bing verfasserin aut Miao, Ze-Hong verfasserin aut Enthalten in Biochemical pharmacology Amsterdam [u.a.] : Elsevier Science, 1958 185 Online-Ressource (DE-627)30631777X (DE-600)1496199-4 (DE-576)081952929 1873-2968 nnns volume:185 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_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 44.38 Pharmakologie AR 185
language	English
source	Enthalten in Biochemical pharmacology 185 volume:185
sourceStr	Enthalten in Biochemical pharmacology 185 volume:185
format_phy_str_mv	Article
bklname	Pharmakologie
institution	findex.gbv.de
topic_facet	N2817 Bivalent BET inhibitors Monovalent BET inhibitors TAF1 Anticancer activity
dewey-raw	610
isfreeaccess_bool	false
container_title	Biochemical pharmacology
authorswithroles_txt_mv	Wu, Qian @@aut@@ Chen, Dan-Qi @@aut@@ Sun, Lin @@aut@@ Huan, Xia-Juan @@aut@@ Bao, Xu-Bin @@aut@@ Tian, Chang-Qing @@aut@@ Hu, Jianping @@aut@@ Lv, Kai-Kai @@aut@@ Wang, Ying-Qing @@aut@@ Xiong, Bing @@aut@@ Miao, Ze-Hong @@aut@@
publishDateDaySort_date	2021-01-01T00:00:00Z
hierarchy_top_id	30631777X
dewey-sort	3610
id	ELV005736463
language_de	englisch
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author	Wu, Qian
spellingShingle	Wu, Qian ddc 610 fid PHARM bkl 44.38 misc N2817 misc Bivalent BET inhibitors misc Monovalent BET inhibitors misc TAF1 misc Anticancer activity Novel bivalent BET inhibitor N2817 exhibits potent anticancer activity and inhibits TAF1
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topic_title	610 DE-600 PHARM DE-84 fid 44.38 bkl Novel bivalent BET inhibitor N2817 exhibits potent anticancer activity and inhibits TAF1 N2817 Bivalent BET inhibitors Monovalent BET inhibitors TAF1 Anticancer activity
topic	ddc 610 fid PHARM bkl 44.38 misc N2817 misc Bivalent BET inhibitors misc Monovalent BET inhibitors misc TAF1 misc Anticancer activity
topic_unstemmed	ddc 610 fid PHARM bkl 44.38 misc N2817 misc Bivalent BET inhibitors misc Monovalent BET inhibitors misc TAF1 misc Anticancer activity
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title	Novel bivalent BET inhibitor N2817 exhibits potent anticancer activity and inhibits TAF1
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title_full	Novel bivalent BET inhibitor N2817 exhibits potent anticancer activity and inhibits TAF1
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author_browse	Wu, Qian Chen, Dan-Qi Sun, Lin Huan, Xia-Juan Bao, Xu-Bin Tian, Chang-Qing Hu, Jianping Lv, Kai-Kai Wang, Ying-Qing Xiong, Bing Miao, Ze-Hong
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title_sort	novel bivalent bet inhibitor n2817 exhibits potent anticancer activity and inhibits taf1
title_auth	Novel bivalent BET inhibitor N2817 exhibits potent anticancer activity and inhibits TAF1
abstract	Bromodomain and extra-terminal domain (BET) family proteins are promising anticancer targets. Most BET inhibitors in clinical trials are monovalent. They competitively bind to one of the bromodomains (BD1 and BD2) in BET proteins and exhibit relatively weak anticancer activity, poor pharmacokinetics, and low metabolic stability. Here, we evaluated the anticancer activity of a novel bivalent BET inhibitor, N2817, which consists of two molecules of the monovalent BET inhibitor 8124-053 connected by a common piperazine ring, rendering a long linker unnecessary. Compared with ABBV-075, one of the potent monovalent BET inhibitors reported to date, N2817 showed greater potency in inhibiting proliferation, arresting cell-cycle, inducing apoptosis, and suppressing the growth of tumor xenografts. Moreover, N2817 showed high metabolic stability, a relatively long half-life, and no brain penetration after oral administration. Additionally, N2817 directly bound and inhibited another BD-containing protein, TAF1 (BD2), as evidenced by a reduction in mRNA and protein levels. TAF1 inhibition contributed to the anticancer effect of N2817. Therefore, this study offers a new paradigm for designing bivalent BET inhibitors and introduces a novel potent bivalent BET inhibitor and a new anticancer mechanism.
abstractGer	Bromodomain and extra-terminal domain (BET) family proteins are promising anticancer targets. Most BET inhibitors in clinical trials are monovalent. They competitively bind to one of the bromodomains (BD1 and BD2) in BET proteins and exhibit relatively weak anticancer activity, poor pharmacokinetics, and low metabolic stability. Here, we evaluated the anticancer activity of a novel bivalent BET inhibitor, N2817, which consists of two molecules of the monovalent BET inhibitor 8124-053 connected by a common piperazine ring, rendering a long linker unnecessary. Compared with ABBV-075, one of the potent monovalent BET inhibitors reported to date, N2817 showed greater potency in inhibiting proliferation, arresting cell-cycle, inducing apoptosis, and suppressing the growth of tumor xenografts. Moreover, N2817 showed high metabolic stability, a relatively long half-life, and no brain penetration after oral administration. Additionally, N2817 directly bound and inhibited another BD-containing protein, TAF1 (BD2), as evidenced by a reduction in mRNA and protein levels. TAF1 inhibition contributed to the anticancer effect of N2817. Therefore, this study offers a new paradigm for designing bivalent BET inhibitors and introduces a novel potent bivalent BET inhibitor and a new anticancer mechanism.
abstract_unstemmed	Bromodomain and extra-terminal domain (BET) family proteins are promising anticancer targets. Most BET inhibitors in clinical trials are monovalent. They competitively bind to one of the bromodomains (BD1 and BD2) in BET proteins and exhibit relatively weak anticancer activity, poor pharmacokinetics, and low metabolic stability. Here, we evaluated the anticancer activity of a novel bivalent BET inhibitor, N2817, which consists of two molecules of the monovalent BET inhibitor 8124-053 connected by a common piperazine ring, rendering a long linker unnecessary. Compared with ABBV-075, one of the potent monovalent BET inhibitors reported to date, N2817 showed greater potency in inhibiting proliferation, arresting cell-cycle, inducing apoptosis, and suppressing the growth of tumor xenografts. Moreover, N2817 showed high metabolic stability, a relatively long half-life, and no brain penetration after oral administration. Additionally, N2817 directly bound and inhibited another BD-containing protein, TAF1 (BD2), as evidenced by a reduction in mRNA and protein levels. TAF1 inhibition contributed to the anticancer effect of N2817. Therefore, this study offers a new paradigm for designing bivalent BET inhibitors and introduces a novel potent bivalent BET inhibitor and a new anticancer mechanism.
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title_short	Novel bivalent BET inhibitor N2817 exhibits potent anticancer activity and inhibits TAF1
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author2	Chen, Dan-Qi Sun, Lin Huan, Xia-Juan Bao, Xu-Bin Tian, Chang-Qing Hu, Jianping Lv, Kai-Kai Wang, Ying-Qing Xiong, Bing Miao, Ze-Hong
author2Str	Chen, Dan-Qi Sun, Lin Huan, Xia-Juan Bao, Xu-Bin Tian, Chang-Qing Hu, Jianping Lv, Kai-Kai Wang, Ying-Qing Xiong, Bing Miao, Ze-Hong
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up_date	2024-07-06T18:59:13.908Z
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Novel bivalent BET inhibitor N2817 exhibits potent anticancer activity and inhibits TAF1

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