2. Academic Validation
  3. Discovery of a Series of 7-Azaindoles as Potent and Highly Selective CDK9 Inhibitors for Transient Target Engagement

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

  • J Med Chem. 2021 Oct 28;64(20):15189-15213. doi: 10.1021/acs.jmedchem.1c01249.
Bernard Barlaam 1,  Chris De Savi 2,  Allan Dishington 1,  Lisa Drew 2,  Andrew D Ferguson 3,  Douglas Ferguson 2,  Chungang Gu 2,  Sudhir Hande 2,  Lorraine Hassall 1,  Janet Hawkins 1,  Alexander W Hird 2,  Jane Holmes 1,  Michelle L Lamb 2,  Andrew S Lister 1,  Thomas M McGuire 1,  Jane E Moore 1,  Nichole O'Connell 3,  Anil Patel 1,  Kurt G Pike 1,  Ujjal Sarkar 2,  Wenlin Shao 2,  Darren Stead 1,  Jeffrey G Varnes 2,  Melissa M Vasbinder 2,  Lei Wang 4,  Liangwei Wu 4,  Lin Xue 4,  Bin Yang 2,  Tieguang Yao 4
Affiliations

Affiliations

  • 1 Oncology R&D, AstraZeneca, Cambridge CB4 0WG, United Kingdom.
  • 2 Oncology R&D, AstraZeneca, Boston, Massachusetts 02451, United States.
  • 3 Discovery Sciences, AstraZeneca, Boston, Massachusetts 02451, United States.
  • 4 Pharmaron Beijing Co., Ltd., 6 Taihe Road BDA, Beijing 100176, P. R. China.
PMID: 34647738 DOI: 10.1021/acs.jmedchem.1c01249
Abstract

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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-139980
    99.22%, CDK9抑制剂
    CDK
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