Eighteen 5,7-Dihalo-8-quinolinol and 2,2′-Bipyridine Co(II) Complexes as a New Class of Promising Anticancer Agents
Refractory disease and side effects associated with traditional
platinum-based cancer chemotherapy have prompted research into alternative
transitional metal complexes with improved therapeutic profiles. To
this end, Meng et al. (DOI: 10.1021/acsmedchemlett.9b00356) detail in their letter the development and characterization of
a collection of cobalt complexes featuring mixed halogenated 8-quinolinol
and bipyridyl ligands with anticancer potential. A panel of cancer
cell lines was surveyed using an MTT assay, revealing a spectrum of
in vitro activity that was most notable with complex Co7. The compound
showed subnanomolar cytotoxic potency against HeLa cancer cells with
high selectivity against normal hepatocytes. A significant inhibitory
effect of Co7 was observed on telomerase activity and associated oncogenic
regulating factors while the compound also induced mitochondrial dysfunction
and HeLa cell apoptosis. In a murine HeLa xenograft tumor model, reduced
tumor growth was observed in Co7-treated mice by a factor of 1.3 compared
to cisplatin-treated groups without showing signs of toxicity. The
collective data compare favorably to other quinolinol-based metal
complexes as potential anticancer agents.
Structure-Based Design of Selective, Covalent G Protein-Coupled Receptor Kinase 5 Inhibitors
G-protein coupled receptors,
molecular switches that transmit extracellular
signals to effect cellular processes, are in and of themselves regulated
by GPCR kinases (GRKs) that desensitize and promote GPCR internalization.
The relevance of GRKs has been highlighted due to their specific tissue
distribution, accompanied by their implication in various diseases.
To better understand the role of each GRK and the potential for therapeutic
intervention, research has focused on the discovery of selective inhibitors
of GRKs. Using the cocrystal structures of multiple GRKs with pyrrolopyrimidine-based
compounds, Rowlands and co-workers (10.1021/acsmedchemlett.9b00365) identified a nonconserved cysteine residue specific to the GRK5
subfamily that may covalently bind a suitably designed ligand. In
search of a potent and selective inhibitor of GRK5 which has a role
in heart failure, the pyrrolopyrimidine substructure was modified
to include one of a series of Michael acceptors capable of engaging
the cysteine residue. Analogs bearing reactive warheads were prepared
and assessed against a panel of GRKs, revealing key structure–activity
relationships and opportunities for tuning GRK selectivity. Current
efforts are focused on the evaluation of broader kinase selectivity
outside the GRK collection and improvement of potency.
In Silico Discovery of JMJD6 Inhibitors for Cancer Treatment
The widely distributed superfamily of 2-oxoglutarate-dependent
oxygenases (2-OGXs) catalyze an impressive range of chemical transformations
within cells that influence transcription, nucleic acid repair, oxygen
sensing, lipid metabolism, and collagen and other small molecule biosynthesis.
This broad enzymatic functionality has drawn considerable interest
in the pursuit of small molecule modulators that may offer therapeutic
advantage. In their Letter, Ran and co-workers (10.1021/acsmedchemlett.9b00264) describe the results of their study aimed at identifying inhibitors
of Jumonji C (Jmjc) domain-containing proteins, a subfamily of 2-OGXs
with demethylase activity that has emerged as a promising cancer target.
Specifically, the study zeroed in on JMJD6, the enzymatic activity
of which has been shown to be functionally essential in certain cancers
and for which there are no reported inhibitors. As the Jmjc domain
is highly conserved and frames the iron-containing catalytic site
for 2-OG, the team performed a virtual screen for compounds that would
bind the active site of the Jmcj domain of JMJD6. Using known 2-OG-competitive
inhibitors of Jmjc domain-containing proteins, a pharmacophoric model
was generated to prioritize hits by analyzing key binding features,
and filters were applied to select for druglike compounds. Hits were
then validated in JMJD6 enzymatic assays, revealing one key compound,
WL12, which produced a JMJD6-dependent antiproliferative effect in
liver and cervical cancer cell lines. These results represent the
first reported JMJD6 inhibitor with anticancer activity which will
guide future work in this area.