Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 65, Issue 1, Pages 857-875Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.1c02019
Keywords
-
Categories
Funding
- National Natural Science Foundation of China [82073701, 31900687]
- Natural Science Foundation of Jiangsu Province [BK2019040713]
- Project Program of the State Key Laboratory of Natural Medicines, China Pharmaceutical University [SKLNMZZ202013]
- Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University [2020KFKT-5]
- Double First-Class University Project [CPU2018GF04]
Ask authors/readers for more resources
Researchers discovered and synthesized a potent dual CDK6/PIM1 inhibitor, compound 51, through virtual screening, showing high kinase selectivity, excellent safety profile, and strong potency in reducing AML burden, offering a new direction for AML treatment and a promising lead compound for preclinical studies.
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 pharmaco-phore-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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available