Once considered potential liabilities, the modern era
witnesses
a renaissance of interest in covalent inhibitors in drug discovery.
The available toolbox of electrophilic warheads is limited by constraints
on tuning reactivity and selectivity. Following our work on a class
of ferroptotic agents termed CETZOLEs, we discovered new tunable heterocyclic
electrophiles which are capable of inducing ferroptosis. The biological
evaluation demonstrated that thiazoles with an alkyne electrophile
at the 2-position selectively induce ferroptosis with high potency.
Density functional theory calculations and NMR kinetic studies demonstrated
the ability of our heterocycles to undergo thiol addition, an apparent
prerequisite for cytotoxicity. Chemoproteomic analysis indicated several
potential targets, the most prominent among them being GPX4 protein.
These results were further validated by western blot analysis and
the cellular thermal shift assay. Incorporation of these heterocycles
into appropriate pharmacophores generated highly cytotoxic agents
such as the analogue BCP-T.A, with low nM IC50 values in ferroptosis-sensitive cell lines.
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.
Covalent inhibitors have historically been considered potential liabilities in medicinal chemistry. The modern era witnesses a renaissance of interest in irreversible binders. The available toolbox of electrophilic warheads is limited with constraints on tuning reactivity and selectivity. Following our initial work on a new class of ferroptotic agents termed CETZOLEs, we discovered new tunable heterocyclic electrophiles, which are capable of inducing ferroptosis. Extensive biological evaluation demonstrated that thiazoles with an alkyne electrophile at the 2-position selectively induce ferroptosis with high potency. Density functional theory (DFT) calculations and NMR kinetic studies demonstrated the ability of our heterocycles to undergo thiol addition, which appears to be a prerequisite for cytotoxicity. Chemoproteomic analysis by in-gel fluorescence and pulldown experiments indicated several potential targets, the most prominent among them being GPX4 protein. The results from the proteomic data were further validated by western blot analysis and CETSA. Incorporation of our heterocycles into appropriate pharmacophores generates highly cytotoxic agents such as the analog BCP-T. A, which demonstrated low nM IC50 values in a series of ferroptosis-sensitive cell lines.
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