Discovery of 3,6-disubstituted pyridazines as a novel class of anticancer agents targeting cyclin-dependent kinase 2: synthesis, biological evaluation and in silico insights

In plain language

A novel chemical series of 3,6-disubstituted pyridazines has been synthesised and tested in the laboratory for anticancer effects. In laboratory assays, these compounds restricted the growth of human breast cancer cell lines, namely T-47D and MDA-MB-231, while exhibiting only weak effects on the SKOV-3 ovarian cancer cell line. A specific compound designated 11m showed submicromolar growth inhibition against both breast cancer lines. Further testing of 11m and a related compound, 11l, revealed that they disrupt the cell cycle, trigger programmed cell death, and demonstrate low toxicity towards non-cancerous breast cells. Computational investigations indicated cyclin-dependent kinase 2 as a probable target, which was corroborated by enzyme inhibition tests showing nanomolar potency. Computational assessments also demonstrated that the leading compounds possess acceptable drug-likeness and pharmacokinetic profiles, establishing this molecular scaffold as a foundation for anticancer drug optimisation.

Key takeaways

A series of 3,6-disubstituted pyridazines showed targeted anti-proliferative activity against human breast cancer cells in laboratory tests.
The compound 11m achieved submicromolar potency against two breast cancer cell lines and exhibited high selectivity over non-cancerous cells.
Selected compounds effectively inhibited cyclin-dependent kinase 2, with the most potent candidate showing an inhibitory concentration of 20.1 nanomolar.
Computational modelling confirmed acceptable drug-likeness and absorption, distribution, metabolism, and excretion properties for the lead molecules.

Why it matters

Treating cancer requires therapies that can eliminate tumour cells without harming healthy tissue. By targeting cyclin-dependent kinase 2, these newly synthesised small molecules interfere with the division cycle of breast cancer cells while sparing normal cells. This research identifies promising molecular candidates that could eventually inform the design of safer, more selective breast cancer treatments.

Commercialisation angle

This work is at an early discovery stage, relying on in vitro testing and in silico modelling. The findings could serve pharmaceutical companies and medicinal chemistry researchers seeking lead structures for breast cancer therapies targeting cyclin-dependent kinase 2. Substantial preclinical validation, formulation work, and in vivo safety and efficacy testing remain necessary before any therapeutic application can proceed towards clinical evaluation.

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Abstract

Human health in the current medical era is facing numerous challenges, especially cancer. So, the therapeutic arsenal for cancer should be unremittingly enriched with novel small molecules that selectively target tumour cells with minimal toxicity towards normal cells. In this context, herein a new series of 3,6-disubstituted pyridazines 11a-r has been synthesised and evaluated for in vitro anticancer activity. They possessed good anti-proliferative action towards human breast cancer T-47D (IC50 range: 0.43 ± 0.01 - 35.9 ± 1.18 µM) and MDA-MB-231 (IC50 range: 0.99 ± 0.03 - 34.59 ± 1.13 µM) cell lines, whereas they displayed weak activity against the tested ovarian cancer cell line SKOV-3. Among the studied compounds, the methyltetrahydropyran-bearing pyridazine 11m emerged as the unique submicromolar growth inhibitor herein reported towards both T-47D (IC50 = 0.43 ± 0.01 µM) and MDA-MB-231 (IC50 = 0.99 ± 0.03 µM) cell lines. In addition, the biological results indicated that pyridazines 11l and 11m exerted an efficient alteration within the cell cycle progression as well as induction of apoptosis in both T-47D and MDA-MB-231 cells. Moreover, pyridazines 11l and 11m displayed good mean tumour S. I. values of 13.7 and 16.1 upon assessment of their cytotoxicity towards non-tumorigenic breast MCF-10A cells. Furthermore, an in silico study proposed CDK2 as a probable enzymatic target for pyridazines 11, and explored their binding interactions within the vicinity of CDK2 binding site. Subsequently, pyridazines 11e, 11h, 11l, and 11m were selected to be evaluated for their ability to inhibit CDK2, where they exerted good inhibitory activity (IC50 = 151, 43.8, 55.6 and 20.1 nM, respectively). Finally, the in silico study implied that target pyridazines 11 exhibited not only an efficient anticancer activity but also an acceptable ADME, physicochemical and druglikeness properties, specifically pyridazines 11l and 11m. Overall the obtained results from this study quite sustained our strategy and gave us a robust opportunity for further development and optimisation of 3,6-disubstituted pyridazine scaffold to enrich therapeutic arsenal with efficient and safe anticancer CDK inhibitors.

Research topics

Cancer Mechanisms and Therapy
Synthesis and Characterization of Heterocyclic Compounds
Synthesis and biological activity

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