Abstract
Two novel ferrocene-containing compounds based upon a known MNK1/2 kinase (MAPK-interacting kinase) inhibitor have been synthesized. The compounds were designed to use the unique shape of ferrocene to exploit a large hydrophobic pocket in MNK1/2 that is only partially occupied by the original compound. Screening of the ferrocene analogues showed that both exhibited potent anticancer effects in several breast cancer and AML (acute myeloid leukemia) cell lines, despite a loss of MNK potency. The most potent ferrocene-based compound 5 was further analysed in vitro in MDA-MB-231 (triple negative breast cancer cells). Dose–response curves of compound 5 for 2D assay and 3D assay generated IC50 values (half maximal inhibitory concentration) of 0.55 µM and 1.25 µM, respectively.
Highlights
Cancer is among the leading cause of mortality worldwide and the number of cases are expected to rise due to increases in life expectancy and the adoption of poor lifestyle choices
Structural modelling of compound 1 in the active site of MNK kinase revealed a large hydrophobic pocket that could be exploited with a bulkier group such as a ferrocene
It is unsurprising that compound 1 has no significant effect on cell viability, as the MNK kinases are dispensible for normal development [34]
Summary
Cancer is among the leading cause of mortality worldwide and the number of cases are expected to rise due to increases in life expectancy and the adoption of poor lifestyle choices. Despite significant advances in early screening and targeted treatments, the prognosis for patients with advanced stage cancer remains bleak [1] This is evident for late-stage breast cancer, of which 15% are classified as triple negative breast cancer (TNBC), defined as tumours that lack oestrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression [2]. These cells display highly aggressive clinical behaviour and limited treatment options have led to poor survival rates [3].
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