article · Bioorganic Chemistry
Novel chemical compounds based on pyrolo[2,3-c]pyrazole, pyrolo[2,3-d]pyrimidine, and related structures have been synthesised and evaluated as inhibitors of the CDK2/cyclin A2 enzyme, an important target in cancer treatment. In laboratory tests on breast cancer and hepatocellular carcinoma cell lines, most of the new compounds demonstrated notable cytotoxic activity, performing comparably to or better than the reference drug Sorafenib. Among these, two lead compounds showed potent inhibition of the CDK2 enzyme, successfully reducing CDK2 levels, halting cancer cell cycles, and triggering cell death in breast cancer cells. Crucially, these molecules demonstrated low toxicity toward normal cells. Computational studies, including molecular docking, dynamics simulations, and pharmacokinetic analyses, confirmed that the compounds fit effectively into the enzyme binding site and possess drug-like characteristics suitable for continued drug design.
Cyclin-dependent kinases such as CDK2 play a major role in regulating cell division and can drive tumour growth when altered. Discovering molecules that block this enzyme selectively helps researchers design cancer therapies that destroy malignant cells effectively. Demonstrating that these new compounds spare healthy cells suggests they may offer a safer path forward in treating breast and liver cancers.
This work is at an early discovery stage, providing newly synthesised chemical scaffolds for preclinical oncology drug pipelines. The primary users would be medicinal chemists and pharmaceutical developers focusing on targeted kinase inhibitors for breast and liver cancers. Substantial further work, including in vivo efficacy testing, toxicology assessments, and formulation optimisation, is required before these compounds could advance toward clinical evaluation or commercial development.
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Inhibiting the CDK2/cyclin A2 enzyme has been validated in multiple clinical manifestations related to multiple types of cancer. Herein, novel series of pyrolo[2,3-c]pyrazole, pyrolo[2,3-c]isoaxazole and pyrolo[2,3-d]pyrimidine, pyrolo[3,2-c]pyridine & indole based analogs were designed, synthesized and biologically evaluated for their in vitro antiproliferative activity where the obtained results revealed that most of the newly synthesized compounds showed significant cytotoxic activity towards MCF-7 (breast cancer cell lines) and HepG-2 (hepatocellular carcinoma) with IC50 ranging from 3.20 µM to 10.05 µM & from 2.18 µM to 13.49 µM, respectively, compared to that of Sorafenib (IC50 9.76 & 13.19 µM, respectively). The in vitro inhibitory profile of the most promising compounds (9, 11, 14, 15, 16, 17 and 20) towards CDK2/CyclinA2 was evaluated. Compounds 14 & 15 exhibited potent inhibitory profile against CDK2 with (IC50 0.11 and 0.262 µM, respectively comparable to Sorafenib IC50 0.184 µM. Western blotting of 14 & 15 at MCF-7 cell line confirmed the diminishing activity on CDK2. Furthermore, both compounds exserted a significant cell cycle arrest and apoptosis. Moreover, the normal cell line cytotoxicity for both compounds revealed low cytotoxic results in normal cells rather than cancer cells. Molecular docking and dynamic simulation validated the potentiality of the newly synthesized compounds to have high binding affinity within CDK2 binding pocket. 3DQSAR pharmacophore, in-silico ADME/TOPKAT studies and drug-likeness showed proper pharmacokinetic properties and helped in structure requirements prediction. The obtained model and pattern of substitution could be used for further development of CDK2 inhibitors.
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DOI: 10.1016/j.bioorg.2023.106729
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