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.
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive, incurable cancer with a 20% one-year survival rate. While standard-of-care therapy can prolong life in a small fraction of cases, PDAC is inherently resistant to current treatments and novel therapies are urgently required. Histone deacetylase (HDAC) inhibitors are effective in killing pancreatic cancer cells in in vitro PDAC studies, and although there are a few clinical studies investigating combination therapy including HDAC inhibitors, no HDAC drug or combination therapy with an HDAC drug has been approved for the treatment of PDAC. We developed an inhibitor of HDACs, AES-135, that exhibits nanomolar inhibitory activity against HDAC3, HDAC6, and HDAC11 in biochemical assays. In a 3D co-culture model, AES-135 kills low passage patient-derived tumor spheroids selectively over surrounding cancer-associated fibroblasts (CAFs), and has excellent pharmacokinetic properties in vivo. In an orthotopic murine model of pancreatic cancer, AES-135 prolongs survival significantly, therefore representing a candidate for further preclinical testing.
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.
The HDAC inhibitor 4-tert-butyl-N-(4-(hydroxycarbamoyl)phenyl)benzamide (AES-350, 51) was identified as a promising preclinical candidate for the treatment of acute myeloid leukemia (AML), an aggressive malignancy with a meagre 24% 5-year survival rate. Through screening of low-molecular-weight analogues derived from the previously discovered novel HDAC inhibitor, AES-135, compound 51 demonstrated greater HDAC isoform selectivity, higher cytotoxicity in MV4-11 cells, an improved therapeutic window, and more efficient absorption through cellular and lipid membranes. Compound 51 also demonstrated improved oral bioavailability compared to SAHA in mouse models. A broad spectrum of experiments, including FACS, ELISA, and Western blotting, were performed to support our hypothesis that 51 dose-dependently triggers apoptosis in AML cells through HDAC inhibition.
Histone deacetylase 6 (HDAC6) is involved in multiple regulatory processes, ranging from cellular stress to intracellular transport. Inhibition of aberrant HDAC6 activity in several cancers and neurological diseases has been shown to be efficacious in both preclinical and clinical studies. While selective HDAC6 targeting has been pursued as an alternative to pan-HDAC drugs, identifying truly selective molecular templates has not been trivial. Herein, we report a structure−activity relationship study yielding TO-317, which potently binds HDAC6 catalytic domain 2 (K i = 0.7 nM) and inhibits the enzyme function (IC 50 = 2 nM). TO-317 exhibits 158-fold selectivity for HDAC6 over other HDAC isozymes by binding the catalytic Zn 2+ and, uniquely, making a never seen before direct hydrogen bond with the Zn 2+ coordinating residue, His614. This novel structural motif targeting the second-sphere His614 interaction, observed in a 1.84 Å resolution crystal structure with drHDAC6 from zebrafish, can provide new pharmacophores for identifying enthalpically driven, high-affinity, HDAC6-selective inhibitors.
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