Effective management of advanced cancer requires systemic treatment including small molecules that target unique features of aggressive tumor cells. At the same time, tumors are heterogeneous and current evidence suggests that a subpopulation of tumor cells, called tumor initiating or cancer stem cells, are responsible for metastatic dissemination, tumor relapse and possibly drug resistance. Classical apoptotic drugs are less effective against this critical subpopulation. In the course of generating a library of open-chain epothilones, we discovered a new class of small molecule anticancer agents that has no effect on tubulin but instead kills selected cancer cell lines by harnessing reactive oxygen species to induce ferroptosis. Interestingly, we find that drug sensitivity is highest in tumor cells with a mesenchymal phenotype. Furthermore, these compounds showed enhanced toxicity towards mesenchymal breast cancer populations with cancer stem cell properties
in vitro
. In summary, we have identified a new class of small molecule ferroptotic agents that warrant further investigation.
HDAC
inhibitors are an attractive class of cytotoxic agents for
the design of hybrid molecules. Several HDAC hybrids have emerged
over the years, but none combines HDAC inhibition with ferroptosis,
a combination which is being extensively studied because it leads
to enhanced cytotoxicity and attenuated neuronal toxicity. We combined
the pharmacophores of SAHA and CETZOLE molecules
to design the first-in-class dual mechanism hybrid molecules, which
induce ferroptosis and inhibit HDAC proteins. The involvement of both
mechanisms in cytotoxicity was confirmed by a series of biological
assays. The cytotoxic effects were evaluated in a series of cancer
and neuronal cell lines. Analogue HY-1 demonstrated the
best cytotoxic profile with GI50 values as low as 20 nM.
Although the increase in activity of the hybrids over the combinations
is modest in cellular systems, they have the potential advantage of
homogeneous spatiotemporal distribution in in vivo systems.
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