Discovery of (R)-5-(benzo[d][1,3]dioxol-5-yl)-7-((1-(vinylsulfonyl)pyrrolidin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (B6) as a potent Bmx inhibitor for the treatment of NSCLC

[Display omitted] Described as a Btk inhibitor, ibrutinib also potently inhibits Bmx and EGFR, two good targets for lung cancer. Owing to its high CLogP (4.07) and low aqueous solubility (

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Veröffentlicht in:Bioorganic & medicinal chemistry letters 2017-09, Vol.27 (17), p.4171-4175
Hauptverfasser: He, Linhong, Li, Da, Zhang, Chufeng, Bai, Peng, Chen, Lijuan
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container_end_page 4175
container_issue 17
container_start_page 4171
container_title Bioorganic & medicinal chemistry letters
container_volume 27
creator He, Linhong
Li, Da
Zhang, Chufeng
Bai, Peng
Chen, Lijuan
description [Display omitted] Described as a Btk inhibitor, ibrutinib also potently inhibits Bmx and EGFR, two good targets for lung cancer. Owing to its high CLogP (4.07) and low aqueous solubility (
doi_str_mv 10.1016/j.bmcl.2017.07.009
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Owing to its high CLogP (4.07) and low aqueous solubility (&lt;0.01mg/ml), resulting in unfavorable bioavailability, ibrutinib requires high dosages to achieve good clinical response in the treatment of non-small cell lung cancer (NSCLC). In our effort to improve the CLogP of ibrutinib by structural optimization led to the discovery of a potent anti-cancer agent B6, with beneficial physicochemical parameters (CLogP=2.56, solubility in water≈0.1mg/ml) meeting the principles of oral drugs. B6 exhibited anti-proliferation activities against EGFR-expressing cells, especially the mutant ones, such as H1975 (L858R/T790M, IC50=0.92±0.19μM) and HCC827 (Del119 IC50=0.014±0.01μM). Moreover, B6 significantly slowed down H1975 tumor growth with anti-tumor rate of 73.9% (p&lt;0.01). Enzyme potencies assay demonstrated B6 moderately selectively inhibited Bmx (IC50=35.7±0.1nM) over other kinases. So, as a potent Bmx inhibitor, B6 has the potential to be an efficacious treatment for NSCLC with acquired drug resistance.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2017.07.009</identifier><identifier>PMID: 28734581</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>Antineoplastic Agents - chemical synthesis ; Antineoplastic Agents - chemistry ; Antineoplastic Agents - pharmacology ; Bmx ; Carcinoma, Non-Small-Cell Lung - drug therapy ; Carcinoma, Non-Small-Cell Lung - pathology ; Cell Line, Tumor ; Cell Proliferation - drug effects ; ClogP ; Dose-Response Relationship, Drug ; Drug Discovery ; Drug Screening Assays, Antitumor ; EGFR ; Humans ; Lung Neoplasms - drug therapy ; Lung Neoplasms - pathology ; Molecular Conformation ; NSCLC ; Protein Kinase Inhibitors - chemical synthesis ; Protein Kinase Inhibitors - chemistry ; Protein Kinase Inhibitors - pharmacology ; Protein-Tyrosine Kinases - antagonists &amp; inhibitors ; Protein-Tyrosine Kinases - metabolism ; Solubility ; Structure-Activity Relationship</subject><ispartof>Bioorganic &amp; medicinal chemistry letters, 2017-09, Vol.27 (17), p.4171-4175</ispartof><rights>2017</rights><rights>Copyright © 2017. 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Owing to its high CLogP (4.07) and low aqueous solubility (&lt;0.01mg/ml), resulting in unfavorable bioavailability, ibrutinib requires high dosages to achieve good clinical response in the treatment of non-small cell lung cancer (NSCLC). In our effort to improve the CLogP of ibrutinib by structural optimization led to the discovery of a potent anti-cancer agent B6, with beneficial physicochemical parameters (CLogP=2.56, solubility in water≈0.1mg/ml) meeting the principles of oral drugs. B6 exhibited anti-proliferation activities against EGFR-expressing cells, especially the mutant ones, such as H1975 (L858R/T790M, IC50=0.92±0.19μM) and HCC827 (Del119 IC50=0.014±0.01μM). Moreover, B6 significantly slowed down H1975 tumor growth with anti-tumor rate of 73.9% (p&lt;0.01). Enzyme potencies assay demonstrated B6 moderately selectively inhibited Bmx (IC50=35.7±0.1nM) over other kinases. So, as a potent Bmx inhibitor, B6 has the potential to be an efficacious treatment for NSCLC with acquired drug resistance.</description><subject>Antineoplastic Agents - chemical synthesis</subject><subject>Antineoplastic Agents - chemistry</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Bmx</subject><subject>Carcinoma, Non-Small-Cell Lung - drug therapy</subject><subject>Carcinoma, Non-Small-Cell Lung - pathology</subject><subject>Cell Line, Tumor</subject><subject>Cell Proliferation - drug effects</subject><subject>ClogP</subject><subject>Dose-Response Relationship, Drug</subject><subject>Drug Discovery</subject><subject>Drug Screening Assays, Antitumor</subject><subject>EGFR</subject><subject>Humans</subject><subject>Lung Neoplasms - drug therapy</subject><subject>Lung Neoplasms - pathology</subject><subject>Molecular Conformation</subject><subject>NSCLC</subject><subject>Protein Kinase Inhibitors - chemical synthesis</subject><subject>Protein Kinase Inhibitors - chemistry</subject><subject>Protein Kinase Inhibitors - pharmacology</subject><subject>Protein-Tyrosine Kinases - antagonists &amp; 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Li, Da ; Zhang, Chufeng ; Bai, Peng ; Chen, Lijuan</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c356t-4c6c2682147d7754fa2490d17fb5b7bad1ddd57f0cb6e73a80b673f70ec14fde3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Antineoplastic Agents - chemical synthesis</topic><topic>Antineoplastic Agents - chemistry</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Bmx</topic><topic>Carcinoma, Non-Small-Cell Lung - drug therapy</topic><topic>Carcinoma, Non-Small-Cell Lung - pathology</topic><topic>Cell Line, Tumor</topic><topic>Cell Proliferation - drug effects</topic><topic>ClogP</topic><topic>Dose-Response Relationship, Drug</topic><topic>Drug Discovery</topic><topic>Drug Screening Assays, Antitumor</topic><topic>EGFR</topic><topic>Humans</topic><topic>Lung Neoplasms - drug therapy</topic><topic>Lung Neoplasms - pathology</topic><topic>Molecular Conformation</topic><topic>NSCLC</topic><topic>Protein Kinase Inhibitors - chemical synthesis</topic><topic>Protein Kinase Inhibitors - chemistry</topic><topic>Protein Kinase Inhibitors - pharmacology</topic><topic>Protein-Tyrosine Kinases - antagonists &amp; inhibitors</topic><topic>Protein-Tyrosine Kinases - metabolism</topic><topic>Solubility</topic><topic>Structure-Activity Relationship</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>He, Linhong</creatorcontrib><creatorcontrib>Li, Da</creatorcontrib><creatorcontrib>Zhang, Chufeng</creatorcontrib><creatorcontrib>Bai, Peng</creatorcontrib><creatorcontrib>Chen, Lijuan</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Bioorganic &amp; medicinal chemistry letters</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>He, Linhong</au><au>Li, Da</au><au>Zhang, Chufeng</au><au>Bai, Peng</au><au>Chen, Lijuan</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Discovery of (R)-5-(benzo[d][1,3]dioxol-5-yl)-7-((1-(vinylsulfonyl)pyrrolidin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (B6) as a potent Bmx inhibitor for the treatment of NSCLC</atitle><jtitle>Bioorganic &amp; medicinal chemistry letters</jtitle><addtitle>Bioorg Med Chem Lett</addtitle><date>2017-09-01</date><risdate>2017</risdate><volume>27</volume><issue>17</issue><spage>4171</spage><epage>4175</epage><pages>4171-4175</pages><issn>0960-894X</issn><eissn>1464-3405</eissn><abstract>[Display omitted] Described as a Btk inhibitor, ibrutinib also potently inhibits Bmx and EGFR, two good targets for lung cancer. Owing to its high CLogP (4.07) and low aqueous solubility (&lt;0.01mg/ml), resulting in unfavorable bioavailability, ibrutinib requires high dosages to achieve good clinical response in the treatment of non-small cell lung cancer (NSCLC). In our effort to improve the CLogP of ibrutinib by structural optimization led to the discovery of a potent anti-cancer agent B6, with beneficial physicochemical parameters (CLogP=2.56, solubility in water≈0.1mg/ml) meeting the principles of oral drugs. B6 exhibited anti-proliferation activities against EGFR-expressing cells, especially the mutant ones, such as H1975 (L858R/T790M, IC50=0.92±0.19μM) and HCC827 (Del119 IC50=0.014±0.01μM). Moreover, B6 significantly slowed down H1975 tumor growth with anti-tumor rate of 73.9% (p&lt;0.01). Enzyme potencies assay demonstrated B6 moderately selectively inhibited Bmx (IC50=35.7±0.1nM) over other kinases. So, as a potent Bmx inhibitor, B6 has the potential to be an efficacious treatment for NSCLC with acquired drug resistance.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>28734581</pmid><doi>10.1016/j.bmcl.2017.07.009</doi><tpages>5</tpages></addata></record>
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ispartof Bioorganic & medicinal chemistry letters, 2017-09, Vol.27 (17), p.4171-4175
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subjects Antineoplastic Agents - chemical synthesis
Antineoplastic Agents - chemistry
Antineoplastic Agents - pharmacology
Bmx
Carcinoma, Non-Small-Cell Lung - drug therapy
Carcinoma, Non-Small-Cell Lung - pathology
Cell Line, Tumor
Cell Proliferation - drug effects
ClogP
Dose-Response Relationship, Drug
Drug Discovery
Drug Screening Assays, Antitumor
EGFR
Humans
Lung Neoplasms - drug therapy
Lung Neoplasms - pathology
Molecular Conformation
NSCLC
Protein Kinase Inhibitors - chemical synthesis
Protein Kinase Inhibitors - chemistry
Protein Kinase Inhibitors - pharmacology
Protein-Tyrosine Kinases - antagonists & inhibitors
Protein-Tyrosine Kinases - metabolism
Solubility
Structure-Activity Relationship
title Discovery of (R)-5-(benzo[d][1,3]dioxol-5-yl)-7-((1-(vinylsulfonyl)pyrrolidin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (B6) as a potent Bmx inhibitor for the treatment of NSCLC
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