Explanatory review on pyrimidine/fused pyrimidine derivatives as anticancer agents targeting Src kinase

Abstract

The pyrimidine and fused pyrimidine ring systems play vital roles to inhibit the c-Src kinase. The Src kinase is made of different domains but the kinase domain is responsible for inhibition of Src kinase. In which the kinase domain is the main domain that is made of several amino acids. The Src kinase is inhibited by its inhibitors when it is activated by phosphorylation. Although dysregulation of Src kinase caused cancer in the late nineteenth century, medicinal chemists have not explored it extensively; therefore it is still regarded as a cult pathway. There are numerous FDA-approved drugs on the market, yet novel anticancer drugs are still in demand. Existing medications have adverse effects and drug resistance owing to rapid protein mutation. In this review, we discussed the activation process of Src kinase, chemistry of pyrimidine ring and its different synthetic routes, as well as the recent development in c-Src kinase inhibitors containing pyrimidine and their biological activity, SAR, and selectivity. The c-Src binding pocket has been predicted in detail to discover the vital amino acids which will interact with inhibitors. The potent derivatives were docked to discover the binding pattern. The derivative 2 established three hydrogen bonds with the amino acid residues Thr341 and Gln278 and had the greatest binding energy of −13.0 kcal/mol. The top docked molecules were further studied for ADMET studies. The derivative 1, 2, and 43 did not show any violation of Lipinski’s rule. All derivatives used for the prediction of toxicity showed toxicity.

Communicated by Ramaswamy H. Sarma

Keywords:

• Src kinase
• molecular docking
• biological activity
• anticancer agent

Author contributions

Ghanshyam Teli (Corresponding author): Conceptualization, original draft preparation, collection, and sorting of data. Rohit Pal: Primary editing, design, and supervising. Lalmohan Maji, Sindhuja Sengupta: Proof reading and scientific evaluation: Gurubasavaraja Swamy Purawarga Matada (Corresponding author): Supervising the work and scientific advisor.

Disclosure statement

No potential conflict of interest was reported by the authors..

Geolocation information

Bengaluru, Karnataka, India

Additional information

Funding

This study was supported by the Acharya & B M Reddy College of Pharmacy in Bengaluru and the ICMR under grants (No. 5/13/79/2020/NCD-III and No. 5/13/12/2020/NCD-III)