Rational Design and Development of Novel CDK9 Inhibitors for the Treatment of Acute Myeloid Leukemia
CDK9 is an essential drug target correlated to the development of acute myeloid leukemia (AML). Starting from the hit compound 10, which was discovered through a screening of our in-house compound library, the structural modifications were carried out based on the bioisosterism and scaffold hopping...
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| Veröffentlicht in: | Journal of medicinal chemistry 2021-10, Vol.64 (19), p.14647-14663 |
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| container_title | Journal of medicinal chemistry |
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| creator | Han, Xu Song, Ning Saidahmatov, Abdusaid Wang, Peipei Wang, Yong Hu, Xiaobei Kan, Weijuan Zhu, Wei Gao, Lixin Zeng, Mingjie Wang, Yujie Li, Chunpu Li, Jia Liu, Hong Zhou, Yubo Wang, Jiang |
| description | CDK9 is an essential drug target correlated to the development of acute myeloid leukemia (AML). Starting from the hit compound 10, which was discovered through a screening of our in-house compound library, the structural modifications were carried out based on the bioisosterism and scaffold hopping strategies. Consequently, compound 37 displayed the optimal CDK9 inhibitory activity with an IC50 value of 5.41 nM, which was nearly 1500-fold higher than compound 10. In addition, compound 37 exhibited significant antiproliferative activity in broad cancer cell lines. Further investigation of in vivo properties demonstrated that compound 37 could be orally administrated with an acceptable bioavailability (F = 33.7%). In MV-4-11 subcutaneous xenograft mouse model, compound 37 (7.5 mg/kg) could significantly suppress the tumor progression with a T/C value of 27.80%. Compound 37 represents a promising lead compound for the development of a novel class of CDK9 inhibitors for the treatment of acute myeloid leukemia. |
| doi_str_mv | 10.1021/acs.jmedchem.1c01148 |
| format | Article |
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Starting from the hit compound 10, which was discovered through a screening of our in-house compound library, the structural modifications were carried out based on the bioisosterism and scaffold hopping strategies. Consequently, compound 37 displayed the optimal CDK9 inhibitory activity with an IC50 value of 5.41 nM, which was nearly 1500-fold higher than compound 10. In addition, compound 37 exhibited significant antiproliferative activity in broad cancer cell lines. Further investigation of in vivo properties demonstrated that compound 37 could be orally administrated with an acceptable bioavailability (F = 33.7%). In MV-4-11 subcutaneous xenograft mouse model, compound 37 (7.5 mg/kg) could significantly suppress the tumor progression with a T/C value of 27.80%. Compound 37 represents a promising lead compound for the development of a novel class of CDK9 inhibitors for the treatment of acute myeloid leukemia.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/acs.jmedchem.1c01148</identifier><identifier>PMID: 34477384</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Antineoplastic Agents - chemistry ; Antineoplastic Agents - pharmacology ; Antineoplastic Agents - therapeutic use ; Apoptosis - drug effects ; Cell Line, Tumor ; Cell Proliferation - drug effects ; Cyclin-Dependent Kinase 9 - antagonists & inhibitors ; Drug Design ; High-Throughput Screening Assays ; Humans ; Leukemia, Myeloid, Acute - drug therapy ; Leukemia, Myeloid, Acute - pathology ; Protein Kinase Inhibitors - chemistry ; Protein Kinase Inhibitors - pharmacokinetics ; Protein Kinase Inhibitors - pharmacology ; Protein Kinase Inhibitors - therapeutic use ; Structure-Activity Relationship</subject><ispartof>Journal of medicinal chemistry, 2021-10, Vol.64 (19), p.14647-14663</ispartof><rights>2021 American Chemical Society</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a348t-f4af1ca45bd34e99a369187648ed04bf62295f11520b68427b39f5936b29a9f3</citedby><cites>FETCH-LOGICAL-a348t-f4af1ca45bd34e99a369187648ed04bf62295f11520b68427b39f5936b29a9f3</cites><orcidid>0000-0003-1705-4905 ; 0000-0003-3685-6268</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/acs.jmedchem.1c01148$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/acs.jmedchem.1c01148$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,780,784,2765,27076,27924,27925,56738,56788</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34477384$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Han, Xu</creatorcontrib><creatorcontrib>Song, Ning</creatorcontrib><creatorcontrib>Saidahmatov, Abdusaid</creatorcontrib><creatorcontrib>Wang, Peipei</creatorcontrib><creatorcontrib>Wang, Yong</creatorcontrib><creatorcontrib>Hu, Xiaobei</creatorcontrib><creatorcontrib>Kan, Weijuan</creatorcontrib><creatorcontrib>Zhu, Wei</creatorcontrib><creatorcontrib>Gao, Lixin</creatorcontrib><creatorcontrib>Zeng, Mingjie</creatorcontrib><creatorcontrib>Wang, Yujie</creatorcontrib><creatorcontrib>Li, Chunpu</creatorcontrib><creatorcontrib>Li, Jia</creatorcontrib><creatorcontrib>Liu, Hong</creatorcontrib><creatorcontrib>Zhou, Yubo</creatorcontrib><creatorcontrib>Wang, Jiang</creatorcontrib><title>Rational Design and Development of Novel CDK9 Inhibitors for the Treatment of Acute Myeloid Leukemia</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>CDK9 is an essential drug target correlated to the development of acute myeloid leukemia (AML). Starting from the hit compound 10, which was discovered through a screening of our in-house compound library, the structural modifications were carried out based on the bioisosterism and scaffold hopping strategies. Consequently, compound 37 displayed the optimal CDK9 inhibitory activity with an IC50 value of 5.41 nM, which was nearly 1500-fold higher than compound 10. In addition, compound 37 exhibited significant antiproliferative activity in broad cancer cell lines. Further investigation of in vivo properties demonstrated that compound 37 could be orally administrated with an acceptable bioavailability (F = 33.7%). In MV-4-11 subcutaneous xenograft mouse model, compound 37 (7.5 mg/kg) could significantly suppress the tumor progression with a T/C value of 27.80%. Compound 37 represents a promising lead compound for the development of a novel class of CDK9 inhibitors for the treatment of acute myeloid leukemia.</description><subject>Antineoplastic Agents - chemistry</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Antineoplastic Agents - therapeutic use</subject><subject>Apoptosis - drug effects</subject><subject>Cell Line, Tumor</subject><subject>Cell Proliferation - drug effects</subject><subject>Cyclin-Dependent Kinase 9 - antagonists & inhibitors</subject><subject>Drug Design</subject><subject>High-Throughput Screening Assays</subject><subject>Humans</subject><subject>Leukemia, Myeloid, Acute - drug therapy</subject><subject>Leukemia, Myeloid, Acute - pathology</subject><subject>Protein Kinase Inhibitors - chemistry</subject><subject>Protein Kinase Inhibitors - pharmacokinetics</subject><subject>Protein Kinase Inhibitors - pharmacology</subject><subject>Protein Kinase Inhibitors - therapeutic use</subject><subject>Structure-Activity Relationship</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kMlOwzAURS0EoqXwBwh5ySbFUwYvq5ahooCEuo-c5JmmJHGxHaT-PS5tWbKyLZ97n95B6JqSMSWM3qnSjdctVOUK2jEtCaUiO0FDGjMSiYyIUzQkhLGIJYwP0IVza0IIp4yfowEXIk15Joaoele-Np1q8Axc_dFh1VXh-g2N2bTQeWw0fjXhiaezZ4nn3aouam-sw9pY7FeAlxaUP6KTsveAX7YhXld4Af0ntLW6RGdaNQ6uDucILR_ul9OnaPH2OJ9OFpHiIvORFkrTUom4qLgAKRVPJM3SRGRQEVHohDEZa7rbsEgywdKCSx1LnhRMKqn5CN3uazfWfPXgfN7WroSmUR2Y3uUsTiTPOJE0oGKPltY4Z0HnG1u3ym5zSvKd3jzozY9684PeELs5TOiL8PcXOvoMANkDv3HT22DW_d_5AxRViN0</recordid><startdate>20211014</startdate><enddate>20211014</enddate><creator>Han, Xu</creator><creator>Song, Ning</creator><creator>Saidahmatov, Abdusaid</creator><creator>Wang, Peipei</creator><creator>Wang, Yong</creator><creator>Hu, Xiaobei</creator><creator>Kan, Weijuan</creator><creator>Zhu, Wei</creator><creator>Gao, Lixin</creator><creator>Zeng, Mingjie</creator><creator>Wang, Yujie</creator><creator>Li, Chunpu</creator><creator>Li, Jia</creator><creator>Liu, Hong</creator><creator>Zhou, Yubo</creator><creator>Wang, Jiang</creator><general>American Chemical Society</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0003-1705-4905</orcidid><orcidid>https://orcid.org/0000-0003-3685-6268</orcidid></search><sort><creationdate>20211014</creationdate><title>Rational Design and Development of Novel CDK9 Inhibitors for the Treatment of Acute Myeloid Leukemia</title><author>Han, Xu ; Song, Ning ; Saidahmatov, Abdusaid ; Wang, Peipei ; Wang, Yong ; Hu, Xiaobei ; Kan, Weijuan ; Zhu, Wei ; Gao, Lixin ; Zeng, Mingjie ; Wang, Yujie ; Li, Chunpu ; Li, Jia ; Liu, Hong ; Zhou, Yubo ; Wang, Jiang</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a348t-f4af1ca45bd34e99a369187648ed04bf62295f11520b68427b39f5936b29a9f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Antineoplastic Agents - chemistry</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Antineoplastic Agents - therapeutic use</topic><topic>Apoptosis - drug effects</topic><topic>Cell Line, Tumor</topic><topic>Cell Proliferation - drug effects</topic><topic>Cyclin-Dependent Kinase 9 - antagonists & inhibitors</topic><topic>Drug Design</topic><topic>High-Throughput Screening Assays</topic><topic>Humans</topic><topic>Leukemia, Myeloid, Acute - drug therapy</topic><topic>Leukemia, Myeloid, Acute - pathology</topic><topic>Protein Kinase Inhibitors - chemistry</topic><topic>Protein Kinase Inhibitors - pharmacokinetics</topic><topic>Protein Kinase Inhibitors - pharmacology</topic><topic>Protein Kinase Inhibitors - therapeutic use</topic><topic>Structure-Activity Relationship</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Han, Xu</creatorcontrib><creatorcontrib>Song, Ning</creatorcontrib><creatorcontrib>Saidahmatov, Abdusaid</creatorcontrib><creatorcontrib>Wang, Peipei</creatorcontrib><creatorcontrib>Wang, Yong</creatorcontrib><creatorcontrib>Hu, Xiaobei</creatorcontrib><creatorcontrib>Kan, Weijuan</creatorcontrib><creatorcontrib>Zhu, Wei</creatorcontrib><creatorcontrib>Gao, Lixin</creatorcontrib><creatorcontrib>Zeng, Mingjie</creatorcontrib><creatorcontrib>Wang, Yujie</creatorcontrib><creatorcontrib>Li, Chunpu</creatorcontrib><creatorcontrib>Li, Jia</creatorcontrib><creatorcontrib>Liu, Hong</creatorcontrib><creatorcontrib>Zhou, Yubo</creatorcontrib><creatorcontrib>Wang, Jiang</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>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Han, Xu</au><au>Song, Ning</au><au>Saidahmatov, Abdusaid</au><au>Wang, Peipei</au><au>Wang, Yong</au><au>Hu, Xiaobei</au><au>Kan, Weijuan</au><au>Zhu, Wei</au><au>Gao, Lixin</au><au>Zeng, Mingjie</au><au>Wang, Yujie</au><au>Li, Chunpu</au><au>Li, Jia</au><au>Liu, Hong</au><au>Zhou, Yubo</au><au>Wang, Jiang</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Rational Design and Development of Novel CDK9 Inhibitors for the Treatment of Acute Myeloid Leukemia</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2021-10-14</date><risdate>2021</risdate><volume>64</volume><issue>19</issue><spage>14647</spage><epage>14663</epage><pages>14647-14663</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><abstract>CDK9 is an essential drug target correlated to the development of acute myeloid leukemia (AML). Starting from the hit compound 10, which was discovered through a screening of our in-house compound library, the structural modifications were carried out based on the bioisosterism and scaffold hopping strategies. Consequently, compound 37 displayed the optimal CDK9 inhibitory activity with an IC50 value of 5.41 nM, which was nearly 1500-fold higher than compound 10. In addition, compound 37 exhibited significant antiproliferative activity in broad cancer cell lines. Further investigation of in vivo properties demonstrated that compound 37 could be orally administrated with an acceptable bioavailability (F = 33.7%). 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| subjects | Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacology Antineoplastic Agents - therapeutic use Apoptosis - drug effects Cell Line, Tumor Cell Proliferation - drug effects Cyclin-Dependent Kinase 9 - antagonists & inhibitors Drug Design High-Throughput Screening Assays Humans Leukemia, Myeloid, Acute - drug therapy Leukemia, Myeloid, Acute - pathology Protein Kinase Inhibitors - chemistry Protein Kinase Inhibitors - pharmacokinetics Protein Kinase Inhibitors - pharmacology Protein Kinase Inhibitors - therapeutic use Structure-Activity Relationship |
| title | Rational Design and Development of Novel CDK9 Inhibitors for the Treatment of Acute Myeloid Leukemia |
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