4 research outputs found
Discovery of Novel Class I Histone Deacetylase Inhibitors with Promising in Vitro and in Vivo Antitumor Activities
A successful structure-based design
of novel cyclic depsipeptides
that selectively target class I HDAC isoforms is described. Compound <b>11</b> has an IC<sub>50</sub> of 2.78 nM for binding to the HDAC1
protein, and the prodrugs <b>12</b> and <b>13</b> also
exhibit promising antiproliferative activities in the nanomolar range
against various cancer cell lines. Compounds <b>12</b> and <b>13</b> show more than 20-fold selectivity toward human cancer
cells over human normal cells in comparison with romidepsin (FK228),
demonstrating low probability of toxic side effects. In addition,
compound <b>13</b> exhibits excellent in vivo anticancer activities in a human prostate carcinoma (Du145) xenograft
model with no observed toxicity. Thus, prodrug <b>13</b> has
therapeutic potential as a new class of anticancer agent for further
clinical translation
Discovery of Novel Class I Histone Deacetylase Inhibitors with Promising in Vitro and in Vivo Antitumor Activities
A successful structure-based design
of novel cyclic depsipeptides
that selectively target class I HDAC isoforms is described. Compound <b>11</b> has an IC<sub>50</sub> of 2.78 nM for binding to the HDAC1
protein, and the prodrugs <b>12</b> and <b>13</b> also
exhibit promising antiproliferative activities in the nanomolar range
against various cancer cell lines. Compounds <b>12</b> and <b>13</b> show more than 20-fold selectivity toward human cancer
cells over human normal cells in comparison with romidepsin (FK228),
demonstrating low probability of toxic side effects. In addition,
compound <b>13</b> exhibits excellent in vivo anticancer activities in a human prostate carcinoma (Du145) xenograft
model with no observed toxicity. Thus, prodrug <b>13</b> has
therapeutic potential as a new class of anticancer agent for further
clinical translation
3âSubstitutedâ<i>N</i>â(4-Hydroxynaphthalen-1-yl)arylsulfonamides as a Novel Class of Selective Mclâ1 Inhibitors: Structure-Based Design, Synthesis, SAR, and Biological Evaluation
Mcl-1, an antiapoptotic member of
the Bcl-2 family of proteins,
is a validated and attractive target for cancer therapy. Overexpression
of Mcl-1 in many cancers results in disease progression and resistance
to current chemotherapeutics. Utilizing high-throughput screening,
compound <b>1</b> was identified as a selective Mcl-1 inhibitor
and its binding to the BH3 binding groove of Mcl-1 was confirmed by
several different, but complementary, biochemical and biophysical
assays. Guided by structure-based drug design and supported by NMR
experiments, comprehensive SAR studies were undertaken and a potent
and selective inhibitor, compound <b>21</b>, was designed which
binds to Mcl-1 with a <i>K</i><sub>i</sub> of 180 nM. Biological
characterization of <b>21</b> showed that it disrupts the interaction
of endogenous Mcl-1 and biotinylated Noxa-BH3 peptide, causes cell
death through a Bak/Bax-dependent mechanism, and selectively sensitizes
EÎź-myc lymphomas overexpressing Mcl-1, but not EÎź-myc
lymphoma cells overexpressing Bcl-2. Treatment of human leukemic cell
lines with compound <b>21</b> resulted in cell death through
activation of caspase-3 and induction of apoptosis
PDB Ligand Conformational Energies Calculated Quantum-Mechanically
We present here a greatly updated version of an earlier
study on the conformational energies of proteinâligand complexes
in the Protein Data Bank (PDB) [Nicklaus et al. <i>Bioorg. Med.
Chem</i>. <b>1995</b>, <i>3</i>, 411â428],
with the goal of improving on all possible aspects such as number
and selection of ligand instances, energy calculations performed,
and additional analyses conducted. Starting from about 357,000 ligand
instances deposited in the 2008 version of the Ligand Expo database
of the experimental 3D coordinates of all small-molecule instances
in the PDB, we created a âhigh-qualityâ subset of ligand
instances by various filtering steps including application of crystallographic
quality criteria and structural unambiguousness. Submission of 640
Gaussian 03 jobs yielded a set of about 415 successfully concluded runs.
We used a stepwise optimization of internal degrees of freedom at
the DFT level of theory with the B3LYP/6-31GÂ(d) basis set and a single-point
energy calculation at B3LYP/6-311++GÂ(3df,2p) after each round of (partial)
optimization to separate energy changes due to bond length stretches
vs bond angle changes vs torsion changes. Even for the most âconservativeâ
choice of all the possible conformational energiesî¸the energy
difference between the conformation in which all internal degrees
of freedom except torsions have been optimized and the fully optimized
conformerî¸significant energy values were found. The range of
0 to âź25 kcal/mol was populated quite evenly and independently
of the crystallographic resolution. A smaller number of âoutliersâ
of yet higher energies were seen only at resolutions above 1.3 Ă
.
The energies showed some correlation with molecular size and flexibility
but not with crystallographic quality metrics such as the Cruickshank
diffraction-component precision index (DPI) and R<sub>free</sub>-R,
or with the ligand instance-specific metrics such as occupancy-weighted
B-factor (OWAB), real-space R factor (RSR), and real-space correlation
coefficient (RSCC). We repeated these calculations with the solvent
model IEFPCM, which yielded energy differences that were generally
somewhat lower than the corresponding vacuum results but did not produce
a qualitatively different picture. Torsional sampling around the crystal
conformation at the molecular mechanics level using the MMFF94s force
field typically led to an increase in energy