ACS Publications. Most Trusted. Most Cited. Most Read
My Activity
CONTENT TYPES

Figure 1Loading Img

Discovery of a Series of 7-Azaindoles as Potent and Highly Selective CDK9 Inhibitors for Transient Target Engagement

  • Bernard Barlaam*
    Bernard Barlaam
    Oncology R&D, AstraZeneca, Cambridge CB4 0WG, United Kingdom
    *Email: [email protected]. Tel: +44(0)1625 237335.
  • Chris De Savi
    Chris De Savi
    Oncology R&D, AstraZeneca, Boston, Massachusetts 02451, United States
  • Allan Dishington
    Allan Dishington
    Oncology R&D, AstraZeneca, Cambridge CB4 0WG, United Kingdom
  • Lisa Drew
    Lisa Drew
    Oncology R&D, AstraZeneca, Boston, Massachusetts 02451, United States
    More by Lisa Drew
  • Andrew D. Ferguson
    Andrew D. Ferguson
    Discovery Sciences, AstraZeneca, Boston, Massachusetts 02451, United States
  • Douglas Ferguson
    Douglas Ferguson
    Oncology R&D, AstraZeneca, Boston, Massachusetts 02451, United States
  • Chungang Gu
    Chungang Gu
    Oncology R&D, AstraZeneca, Boston, Massachusetts 02451, United States
    More by Chungang Gu
  • Sudhir Hande
    Sudhir Hande
    Oncology R&D, AstraZeneca, Boston, Massachusetts 02451, United States
    More by Sudhir Hande
  • Lorraine Hassall
    Lorraine Hassall
    Oncology R&D, AstraZeneca, Cambridge CB4 0WG, United Kingdom
  • Janet Hawkins
    Janet Hawkins
    Oncology R&D, AstraZeneca, Cambridge CB4 0WG, United Kingdom
  • Alexander W. Hird
    Alexander W. Hird
    Oncology R&D, AstraZeneca, Boston, Massachusetts 02451, United States
  • Jane Holmes
    Jane Holmes
    Oncology R&D, AstraZeneca, Cambridge CB4 0WG, United Kingdom
    More by Jane Holmes
  • Michelle L. Lamb
    Michelle L. Lamb
    Oncology R&D, AstraZeneca, Boston, Massachusetts 02451, United States
  • Andrew S. Lister
    Andrew S. Lister
    Oncology R&D, AstraZeneca, Cambridge CB4 0WG, United Kingdom
  • Thomas M. McGuire
    Thomas M. McGuire
    Oncology R&D, AstraZeneca, Cambridge CB4 0WG, United Kingdom
  • Jane E. Moore
    Jane E. Moore
    Oncology R&D, AstraZeneca, Cambridge CB4 0WG, United Kingdom
  • Nichole O’Connell
    Nichole O’Connell
    Discovery Sciences, AstraZeneca, Boston, Massachusetts 02451, United States
  • Anil Patel
    Anil Patel
    Oncology R&D, AstraZeneca, Cambridge CB4 0WG, United Kingdom
    More by Anil Patel
  • Kurt G. Pike
    Kurt G. Pike
    Oncology R&D, AstraZeneca, Cambridge CB4 0WG, United Kingdom
    More by Kurt G. Pike
  • Ujjal Sarkar
    Ujjal Sarkar
    Oncology R&D, AstraZeneca, Boston, Massachusetts 02451, United States
    More by Ujjal Sarkar
  • Wenlin Shao
    Wenlin Shao
    Oncology R&D, AstraZeneca, Boston, Massachusetts 02451, United States
    More by Wenlin Shao
  • Darren Stead
    Darren Stead
    Oncology R&D, AstraZeneca, Cambridge CB4 0WG, United Kingdom
    More by Darren Stead
  • Jeffrey G. Varnes
    Jeffrey G. Varnes
    Oncology R&D, AstraZeneca, Boston, Massachusetts 02451, United States
  • Melissa M. Vasbinder
    Melissa M. Vasbinder
    Oncology R&D, AstraZeneca, Boston, Massachusetts 02451, United States
  • Lei Wang
    Lei Wang
    Pharmaron Beijing Co., Ltd., 6 Taihe Road BDA, Beijing 100176, P. R. China
    More by Lei Wang
  • Liangwei Wu
    Liangwei Wu
    Pharmaron Beijing Co., Ltd., 6 Taihe Road BDA, Beijing 100176, P. R. China
    More by Liangwei Wu
  • Lin Xue
    Lin Xue
    Pharmaron Beijing Co., Ltd., 6 Taihe Road BDA, Beijing 100176, P. R. China
    More by Lin Xue
  • Bin Yang
    Bin Yang
    Oncology R&D, AstraZeneca, Boston, Massachusetts 02451, United States
    More by Bin Yang
  • , and 
  • Tieguang Yao
    Tieguang Yao
    Pharmaron Beijing Co., Ltd., 6 Taihe Road BDA, Beijing 100176, P. R. China
    More by Tieguang Yao
Cite this: J. Med. Chem. 2021, 64, 20, 15189–15213
Publication Date (Web):October 14, 2021
https://doi.org/10.1021/acs.jmedchem.1c01249
Copyright © 2021 American Chemical Society

    Article Views

    3158

    Altmetric

    -

    Citations

    LEARN ABOUT THESE METRICS
    Other access options
    Supporting Info (2)»

    Abstract

    Abstract Image

    Optimization of a series of azabenzimidazoles identified from screening hit 2 and the information gained from a co-crystal structure of the azabenzimidazole-based lead 6 bound to CDK9 led to the discovery of azaindoles as highly potent and selective CDK9 inhibitors. With the goal of discovering a highly selective and potent CDK9 inhibitor administrated intravenously that would enable transient target engagement of CDK9 for the treatment of hematological malignancies, further optimization focusing on physicochemical and pharmacokinetic properties led to azaindoles 38 and 39. These compounds are highly potent and selective CDK9 inhibitors having short half-lives in rodents, suitable physical properties for intravenous administration, and the potential to achieve profound but transient inhibition of CDK9 in vivo.

    Read this article

    To access this article, please review the available access options below.

    Get instant access

    Purchase Access

    Read this article for 48 hours. Check out below using your ACS ID or as a guest.

    Recommended

    Access through Your Institution

    You may have access to this article through your institution.

    Your institution does not have access to this content. You can change your affiliated institution below.

    Supporting Information

    ARTICLE SECTIONS
    Jump To

    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.jmedchem.1c01249.

    • Experimental procedures for synthesis; analysis of reported CDK9 and CDK2 crystal structures and their resolutions; procedures for the determination of physicochemical and DMPK properties; biological testing protocols, data, and associated errors; kinase panel data; and HPLC traces for final compounds (PDF)

    • Molecular formula strings (CSV)

    Accession Codes

    The crystallographic structure of compound 6 bound to CDK9 in complex with cyclin T1 has been deposited under the following code: 7NWK. The authors will release the atomic coordinates and experimental data upon article publication.

    Terms & Conditions

    Most electronic Supporting Information files are available without a subscription to ACS Web Editions. Such files may be downloaded by article for research use (if there is a public use license linked to the relevant article, that license may permit other uses). Permission may be obtained from ACS for other uses through requests via the RightsLink permission system: http://pubs.acs.org/page/copyright/permissions.html.

    Cited By

    This article is cited by 10 publications.

    1. Yuming Zhang, Lianhai Shan, Wentao Tang, Yating Ge, ChengXian Li, Jifa Zhang. Recent Discovery and Development of Inhibitors that Target CDK9 and Their Therapeutic Indications. Journal of Medicinal Chemistry 2024, 67 (7) , 5185-5215. https://doi.org/10.1021/acs.jmedchem.4c00312
    2. Tizhi Wu, Bin Yu, Yifan Xu, Zekun Du, Zhiming Zhang, Yuxiao Wang, Haoming Chen, Li′ao Zhang, Rui Chen, Feihai Ma, Weihong Gong, Sixian Yu, Zhixia Qiu, Hongxi Wu, Xi Xu, Jubo Wang, Zhiyu Li, Jinlei Bian. Discovery of Selective and Potent Macrocyclic CDK9 Inhibitors for the Treatment of Osimertinib-Resistant Non-Small-Cell Lung Cancer. Journal of Medicinal Chemistry 2023, 66 (22) , 15340-15361. https://doi.org/10.1021/acs.jmedchem.3c01400
    3. J. Adam Hendricks, Nigel Beaton, Alexey Chernobrovkin, Eric Miele, Ghaith M. Hamza, Piero Ricchiuto, Ronald C. Tomlinson, Tomas Friman, Cassandra Borenstain, Bernard Barlaam, Sudhir Hande, Michelle L. Lamb, Chris De Savi, Rick Davies, Martin Main, Joakim Hellner, Kristina Beeler, Yuehan Feng, Roland Bruderer, Lukas Reiter, Daniel Martinez Molina, M. Paola Castaldi. Mechanistic Insights into a CDK9 Inhibitor Via Orthogonal Proteomics Methods. ACS Chemical Biology 2022, 17 (1) , 54-67. https://doi.org/10.1021/acschembio.1c00488
    4. Jun Yang, Guang-Ping Liang, Xiong-Li Liu. Synthesis and antitumor activities of 4-(1H-indol-1-yl)-4-oxobutanoic acid spliced podophyllotoxin derivatives. Synthetic Communications 2023, 53 (3) , 262-273. https://doi.org/10.1080/00397911.2023.2164863
    5. Yaoguang Huang, Deping Li, Chang Xu, Chengze Zhu, Limeng Wu, Meiling Shen, Yue Li, Xiaowen Jiang, Wenwu Liu, Qingchun Zhao, Tianshu Ren. Discovery of novel and potent tacrine derivatives as CDK2 inhibitors. New Journal of Chemistry 2022, 46 (43) , 20972-20984. https://doi.org/10.1039/D2NJ03591J
    6. Yaoguang Huang, Wenwu Liu, Shuoqi Huang, Deping Li, Chang Xu, Xiaowen Jiang, Mingyue Liu, Xin Liu, Chengze Zhu, Limeng Wu, Huanhua Chen, Zihua Xu, Qingchun Zhao. Discovery of novel benzofuro[3,2-b]quinoline derivatives as dual CDK2/Topo I inhibitors. Bioorganic Chemistry 2022, 126 , 105870. https://doi.org/10.1016/j.bioorg.2022.105870
    7. Xinren Wang, Xiaoyue Liu, Jianhang Huang, Chenhe Liu, Hongmei Li, Cong Wang, Qianqian Hong, Yan Lei, Jiawei Xia, Ziheng Yu, Ruinan Dong, Junyu Xu, Zhenlin Tu, ChunQi Duan, Shuwen Li, Tao Lu, Weifang Tang, Yadong Chen. Discovery of 2H-benzo[b][1,4]oxazin-3(4H)-one derivatives as potent and selective CDK9 inhibitors that enable transient target engagement for the treatment of hematologic malignancies. European Journal of Medicinal Chemistry 2022, 238 , 114461. https://doi.org/10.1016/j.ejmech.2022.114461
    8. Zhi Huang, Tianqi Wang, Cheng Wang, Yan Fan. CDK9 inhibitors in cancer research. RSC Medicinal Chemistry 2022, 13 (6) , 688-710. https://doi.org/10.1039/D2MD00040G
    9. Fulvio Ciriaco, Nicola Gambacorta, Daniela Trisciuzzi, Orazio Nicolotti. PLATO: A Predictive Drug Discovery Web Platform for Efficient Target Fishing and Bioactivity Profiling of Small Molecules. International Journal of Molecular Sciences 2022, 23 (9) , 5245. https://doi.org/10.3390/ijms23095245
    10. Yi Liu, Leilei Fu, Junhao Wu, Ming Liu, Guan Wang, Bo Liu, Lan Zhang. Transcriptional cyclin-dependent kinases: Potential drug targets in cancer therapy. European Journal of Medicinal Chemistry 2022, 229 , 114056. https://doi.org/10.1016/j.ejmech.2021.114056

    Pair your accounts.

    Export articles to Mendeley

    Get article recommendations from ACS based on references in your Mendeley library.

    Pair your accounts.

    Export articles to Mendeley

    Get article recommendations from ACS based on references in your Mendeley library.

    You’ve supercharged your research process with ACS and Mendeley!

    STEP 1:
    Click to create an ACS ID

    Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

    Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

    Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

    MENDELEY PAIRING EXPIRED
    Your Mendeley pairing has expired. Please reconnect