2. Academic Validation
  3. Discovery of Dual CDK6/PIM1 Inhibitors with a Novel Structure, High Potency, and Favorable Druggability for the Treatment of Acute Myeloid Leukemia

Discovery of Dual CDK6/PIM1 Inhibitors with a Novel Structure, High Potency, and Favorable Druggability for the Treatment of Acute Myeloid Leukemia

  • J Med Chem. 2022 Jan 13;65(1):857-875. doi: 10.1021/acs.jmedchem.1c02019.
Kai Yuan 1 2,  Minghui Ji 1 2,  Shengnan Xie 1 2,  Zhixia Qiu 1 3,  Weijiao Chen 1 2,  Wenjian Min 1 2,  Fei Xia 1 2,  Mingming Zheng 1 2,  Xiao Wang 1 2,  Jiaxing Li 1 2,  Yi Hou 1 2,  Wenbin Kuang 1 2,  Liping Wang 1 2,  Wanjian Gu 4,  Zhiyu Li 1 2,  Peng Yang 1 2
Affiliations

Affiliations

  • 1 State Key Laboratory of Natural Medicines and Jiang Su Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.
  • 2 Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
  • 3 Center of Drug Metabolism and Pharmacokinetics, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China.
  • 4 Department of Clinical Laboratory, Jiangsu Province Hospital of Chinese Medicine, Nanjing 211198, China.
PMID: 34958208 DOI: 10.1021/acs.jmedchem.1c02019
Abstract

Nowadays, the simultaneous inhibition of two or more pathways plays an increasingly important role in Cancer treatment due to the complex and diverse pathogenesis of Cancer, and the combination of the cyclin-dependent kinase 6 (CDK6) inhibitor and PIM1 Inhibitor was found to generate synergistic effects in acute myeloid leukemia (AML) treatment. Therefore, we discovered a novel lead 1 targeting CDK6/PIM1 via pharmacophore-based and structure-based virtual screening, synthesized five different series of new derivates, and obtained a potent and balanced dual CDK6/PIM1 Inhibitor 51, which showed high kinase selectivity. Meanwhile, 51 displayed an excellent safety profile and great pharmacokinetic properties. Furthermore, 51 displayed stronger potency in reducing the burden of AML than palbociclib and SMI-4a in vivo. In summary, we offered a new direction for AML treatment and provided a great lead compound for AML preclinical studies.

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