1. Design, synthesis, and biological evaluation of dinaciclib and CAN508 hybrids as CDK inhibitors.
- Author
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Odeh DM, Allam HA, Baselious F, Mahmoud WR, Odeh MM, Ibrahim HS, Abdel-Aziz HA, and Mohammed ER
- Subjects
- Humans, Cell Line, Tumor, Cyclin-Dependent Kinases antagonists & inhibitors, Structure-Activity Relationship, Pyrimidines pharmacology, Pyrimidines chemistry, Drug Screening Assays, Antitumor, Cyclin-Dependent Kinase 5 antagonists & inhibitors, Cyclin-Dependent Kinase 5 metabolism, Cyclin-Dependent Kinase 9 antagonists & inhibitors, Cyclin-Dependent Kinase 9 metabolism, Pyridinium Compounds pharmacology, Pyridinium Compounds chemistry, Indolizines pharmacology, Indolizines chemistry, Bridged Bicyclo Compounds, Heterocyclic pharmacology, Bridged Bicyclo Compounds, Heterocyclic chemistry, Drug Design, Cyclic N-Oxides pharmacology, Cyclic N-Oxides chemistry, Protein Kinase Inhibitors pharmacology, Protein Kinase Inhibitors chemical synthesis, Protein Kinase Inhibitors chemistry, Molecular Docking Simulation, Antineoplastic Agents pharmacology, Antineoplastic Agents chemical synthesis, Antineoplastic Agents chemistry
- Abstract
The scaffolds of two known CDK inhibitors (CAN508 and dinaciclib) were the starting point for synthesizing two series of pyarazolo[1,5-a]pyrimidines to obtain potent inhibitors with proper selectivity. The study presented four promising compounds; 10d, 10e, 16a, and 16c based on cytotoxic studies. Compound 16a revealed superior activity in the preliminary anticancer screening with GI % = 79.02-99.13 against 15 cancer cell lines at 10 μM from NCI full panel 60 cancer cell lines and was then selected for further investigation. Furthermore, the four compounds revealed good safety profile toward the normal cell lines WI-38. These four compounds were subjected to CDK inhibitory activity against four different isoforms. All of them showed potent inhibition against CDK5/P25 and CDK9/CYCLINT. Compound 10d revealed the best activity against CDK5/P25 (IC
50 = 0.063 µM) with proper selectivity index against CDK1 and CDK2. Compound 16c exhibited the highest inhibitory activity against CDK9/CYCLINT (IC50 = 0.074 µM) with good selectivity index against other isoforms. Finally, docking simulations were performed for compounds 10e and 16c accompanied by molecular dynamic simulations to understand their behavior in the active site of the two CDKs with respect to both CAN508 and dinaciclib., (© 2024 Wiley Periodicals LLC.)- Published
- 2024
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