2. Academic Validation
  3. Rational Design and Development of Novel CDK9 Inhibitors for the Treatment of Acute Myeloid Leukemia

Rational Design and Development of Novel CDK9 Inhibitors for the Treatment of Acute Myeloid Leukemia

  • J Med Chem. 2021 Oct 14;64(19):14647-14663. doi: 10.1021/acs.jmedchem.1c01148.
Xu Han 1 2,  Ning Song 1 2 3,  Abdusaid Saidahmatov 1 2,  Peipei Wang 1,  Yong Wang 1,  Xiaobei Hu 1 2 4,  Weijuan Kan 1,  Wei Zhu 1 2,  Lixin Gao 1,  Mingjie Zeng 1,  Yujie Wang 1,  Chunpu Li 1 2,  Jia Li 1 2 3 4,  Hong Liu 1 2 3,  Yubo Zhou 1 2 4,  Jiang Wang 1 2
Affiliations

Affiliations

  • 1 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China.
  • 2 University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China.
  • 3 School of Life Science and Technology, ShanghaiTech University, 393 Middle Huaxia Road, Shanghai 201210, China.
  • 4 Zhongshan Institute of Drug Discovery, Institution for Drug Discovery Innovation, Chinese Academy of Science, Zhongshan 528400, China.
PMID: 34477384 DOI: 10.1021/acs.jmedchem.1c01148
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%). 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.

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