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  2. Design, synthesis, molecular modeling and evaluation of 2,4-diaminopyrimidine analogues as promising colorectal cancer drugs

Design, synthesis, molecular modeling and evaluation of 2,4-diaminopyrimidine analogues as promising colorectal cancer drugs

  • Bioorg Chem. 2024 Sep 29:153:107854. doi: 10.1016/j.bioorg.2024.107854.
Gopalakrishnan Venkatesan 1 Chong Yong Ping 2 Hong Chen 3 Perumal Srinivasan 4 Aneesh V Karkhanis 5 Giorgia Pastorin 6
Affiliations

Affiliations

  • 1 Department of Pharmacy and Pharmaceutical Sciences, National University of Singapore, Lower Kent Ridge Road, 4 Science Drive 2, 117544, Singapore. Electronic address: gopal.venkatesan@u.nus.edu.
  • 2 Critical Analytics for Manufacturing Personalized-Medicine Programme (CAMP), Singapore-MIT Alliance for Research and Technology, Singapore. 1 CREATE Way, #12-02 CREATE Tower, 138602, Singapore.
  • 3 School of Biological Sciences (SBS), Nanyang Technological University, 60 Nanyang Dr, 637551, Singapore.
  • 4 Department of Biomedical Engineering, National University of Singapore, 4 Engineering Drive 3, Engineering Block 4, 117583, Singapore.
  • 5 Certara UK Ltd., Certara Predictive Technologies Division, Level 2-Acero, 1 Concourse Way, Sheffield S1 2B1, United Kingdom.
  • 6 Department of Pharmacy and Pharmaceutical Sciences, National University of Singapore, Lower Kent Ridge Road, 4 Science Drive 2, 117544, Singapore.
Abstract

The potential of cyclin-dependent kinases (CDKs) as therapeutic targets in Cancer treatment is well established. In this study, we present our investigation into a group of 2,4-diaminopyrimidine derivatives that potently inhibit CDK9 and are cytotoxic when tested in colorectal Cancer cell lines. We designed and synthesized forty analogues by altering substitutions at C-2 and C-4 position of the pyrimidine system. Among them, compounds 16 h and 16j exhibited strong inhibitory potency against both CDK9 Enzymes (IC50 = 11.4 ± 1.4 nM, IC50 = 10.2 ± 1.3 nM respectively) with a significant preference for one over the Other, and cytotoxic potency (IC50 = 61 ± 2 nM, IC50 = 20 ± 1 nM respectively) against HCT-116 was discovered through substantial modifications to its structure. Further investigations revealed that compounds 16 h and 16j were directly bound to CDK9, resulting in the suppression of its downstream signaling pathway. This inhibition of cell proliferation occurred by impeding the progression of the cell cycle and inducing Apoptosis in cells by suppressing the phosphoryl RNA pol II Ser2. Significantly, compound 16 h and 16j effectively suppressed tumor growth in a xenograft mouse model and exhibited no apparent toxicity. This indicates that CDK9 inhibitors hold great potential as a therapeutic approach for colorectal Cancer treatment. Therefore, the aforementioned discoveries are vital for the development of CDK9 inhibitors for the treatment of Cancer.

Keywords

2,4-diaminopyrimidine; Apoptosis; Colorectal Cancer; Cyclin-dependent kinase; Molecular docking.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-168515
    CDK9/Cyclin T1 Inhibitor
    CDK