Design, synthesis, and biological evaluation of dinaciclib and CAN508 hybrids as CDK inhibitors

Dana M Odeh; Heba Abdelrasheed Allam; Fady Baselious; Walaa R Mahmoud; Mohanad M Odeh; Hany S Ibrahim; Hatem A Abdel-Aziz; Eman R Mohammed

doi:10.1002/ddr.22193

Design, synthesis, and biological evaluation of dinaciclib and CAN508 hybrids as CDK inhibitors

Drug Dev Res. 2024 May;85(3):e22193. doi: 10.1002/ddr.22193.

Authors

Dana M Odeh¹, Heba Abdelrasheed Allam¹, Fady Baselious², Walaa R Mahmoud¹, Mohanad M Odeh³, Hany S Ibrahim^{2

4}, Hatem A Abdel-Aziz⁵, Eman R Mohammed¹

Affiliations

¹ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
² Department of Medicinal Chemistry, Institute of Pharmacy, Martin-Luther-University of Halle-Wittenberg, Halle (Saale), Germany.
³ Department of Clinical Pharmacy and Pharmacy Practice, Faculty of Pharmaceutical Sciences, The Hashemite University, Zarqa, Jordan.
⁴ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Egyptian Russian University, Cairo, Egypt.
⁵ Department of Applied Organic Chemistry, National Research Center, Cairo, Dokki, Egypt.

PMID: 38685605
DOI: 10.1002/ddr.22193

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 (IC₅₀ = 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.

Keywords: CAN508; CDK inhibitors; dinaciclib; pyrazolo[1,5‐a]pyrimidines.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents* / chemical synthesis
Antineoplastic Agents* / chemistry
Antineoplastic Agents* / pharmacology
Bridged Bicyclo Compounds, Heterocyclic* / chemistry
Bridged Bicyclo Compounds, Heterocyclic* / pharmacology
Cell Line, Tumor
Cyclic N-Oxides* / chemistry
Cyclic N-Oxides* / pharmacology
Cyclin-Dependent Kinase 5 / antagonists & inhibitors
Cyclin-Dependent Kinase 5 / metabolism
Cyclin-Dependent Kinase 9 / antagonists & inhibitors
Cyclin-Dependent Kinase 9 / metabolism
Cyclin-Dependent Kinases / antagonists & inhibitors
Drug Design*
Drug Screening Assays, Antitumor
Humans
Indolizines* / chemistry
Indolizines* / pharmacology
Molecular Docking Simulation*
Protein Kinase Inhibitors* / chemical synthesis
Protein Kinase Inhibitors* / chemistry
Protein Kinase Inhibitors* / pharmacology
Pyridinium Compounds* / chemistry
Pyridinium Compounds* / pharmacology
Pyrimidines / chemistry
Pyrimidines / pharmacology
Structure-Activity Relationship

Substances

dinaciclib
Pyridinium Compounds
Indolizines
Bridged Bicyclo Compounds, Heterocyclic
Cyclic N-Oxides
Protein Kinase Inhibitors
Antineoplastic Agents
Cyclin-Dependent Kinases
Pyrimidines
Cyclin-Dependent Kinase 5
Cyclin-Dependent Kinase 9