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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Bibliographic Details
Published in:Journal of medicinal chemistry 2021-10, Vol.64 (19), p.14647-14663
Main Authors: 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
Format: Article
Language:English
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
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Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.1c01148