Greater plant defence is predicted to evolve at lower latitudes in response to increased herbivore pressure. However, recent studies question the generality of this pattern. In this study, we tested for genetically based latitudinal clines in resistance to herbivores and underlying defence traits of Oenothera biennis. We grew plants from 137 populations from across the entire native range of O. biennis. Populations from lower latitudes showed greater resistance to multiple specialist and generalist herbivores. These patterns were associated with an increase in total phenolics at lower latitudes. A significant proportion of the phenolics were driven by the concentrations of two major ellagitannins, which exhibited opposing latitudinal clines. Our analyses suggest that these findings are unlikely to be explained by local adaptation of herbivore populations or genetic variation in phenology. Rather greater herbivory at high latitudes can be explained by latitudinal clines in the evolution of plant defences.
Histone
deacetylases (HDACs) are an attractive therapeutic target
for a variety of human diseases. Currently, all four FDA-approved
HDAC-targeting drugs are nonselective, pan-HDAC inhibitors, exhibiting
adverse side effects at therapeutic doses. Although selective HDAC
inhibition has been proposed to mitigate toxicity, the targeted catalytic
domains are highly conserved. Herein, we describe a series of rationally
designed, conformationally constrained, benzanilide foldamers which
selectively bind the catalytic tunnel of HDAC8. The series includes
benzanilides, MMH371, MMH409, and MMH410, which exhibit potent in vitro HDAC8
activity (IC50 = 66, 23, and 66 nM, respectively) and up
to 410-fold selectivity for HDAC8 over the next targeted HDAC. Experimental
and computational analyses of the benzanilide structure docked with
human HDAC8 enzyme showed the adoption of a low-energy L-shaped conformer
that favors HDAC8 selectivity. The conformationally constrained HDAC8
inhibitors present an alternative biological probe for further determining
the clinical utility and safety of pharmacological knockdown of HDAC8
in diseased cells.
Histone deacetylase 6 (HDAC6) has
been targeted in clinical studies
for anticancer effects due to its role in oncogenic transformation
and metastasis. Through a second-generation structure–activity
relationship (SAR) study, the design, and biological evaluation of
the selective HDAC6 inhibitor NN-390 is reported. With
nanomolar HDAC6 potency, >200–550-fold selectivity for HDAC6
in analogous HDAC isoform functional assays, potent intracellular
target engagement, and robust cellular efficacy in cancer cell lines, NN-390 is the first HDAC6-selective inhibitor to show therapeutic
potential in metastatic Group 3 medulloblastoma (MB), an aggressive
pediatric brain tumor often associated with leptomeningeal metastases
and therapy resistance. MB stem cells contribute to these patients’
poor clinical outcomes. NN-390 selectively targets this
cell population with a 44.3-fold therapeutic margin between patient-derived
Group 3 MB cells in comparison to healthy neural stem cells. NN-390 demonstrated a 45-fold increased potency over HDAC6-selective
clinical candidate citarinostat. In summary, HDAC6-selective molecules
demonstrated in vitro therapeutic potential against
Group 3 MB.
Epigenetic targeting
has emerged as an efficacious therapy for
hematological cancers. The rare and incurable T-cell prolymphocytic
leukemia (T-PLL) is known for its aggressive clinical course. Current
epigenetic agents such as histone deacetylase (HDAC) inhibitors are
increasingly used for targeted therapy. Through a structure–activity
relationship (SAR) study, we developed an HDAC6 inhibitor KT-531,
which exhibited higher potency in T-PLL compared to other hematological
cancers. KT-531 displayed strong HDAC6 inhibitory potency and selectivity,
on-target biological activity, and a safe therapeutic window in nontransformed
cell lines. In primary T-PLL patient cells, where
HDAC6
was found to be overexpressed, KT-531 exhibited strong biological
responses, and safety in healthy donor samples. Notably, combination
studies in T-PLL patient samples demonstrated KT-531 synergizes with
approved cancer drugs, bendamustine, idasanutlin, and venetoclax.
Our work suggests HDAC inhibition in T-PLL could afford sufficient
therapeutic windows to achieve durable remission either as stand-alone
or in combination with targeted drugs.
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