3 research outputs found
Fusion of Structure and Ligand Based Methods for Identification of Novel CDK2 Inhibitors
Cyclin dependent kinases play a central role in cell
cycle regulation which makes them a promising target with multifarious
therapeutic potential. CDK2 regulates various events of the eukaryotic
cell division cycle, and the pharmacological evidence indicates that
overexpression of CDK2 causes abnormal cell-cycle regulation, which
is directly associated with hyperproliferation of cancer cells. Therefore,
CDK2 is regarded as a potential target molecule for anticancer medication.
Thus, to decline CDK2 activity by potential lead compounds has proved
to be an effective treatment for cancer. The availability of a large
number of X-ray crystal structures and known inhibitors of CDK2 provides
a gateway to perform efficient computational studies on this target.
With the aim to identify new chemical entities from commercial libraries,
with increased inhibitory potency for CDK2, ligand and structure based
computational drug designing approaches were applied. A druglike library
of 50,000 compounds from ChemDiv and ChemBridge databases was screened
against CDK2, and 110 compounds were identified using the parallel
application of these models. On <i>in vitro</i> evaluation
of 40 compounds, seven compounds were found to have more than 50%
inhibition at 10 μM. MD studies of the hits revealed the stability
of these inhibitors and pivotal role of Glu81 and Leu83 for binding
with CDK2. The overall study resulted in the identification of four
new chemical entities possessing CDK2 inhibitory activity
Dual Targeted Polymeric Nanoparticles Based on Tumor Endothelium and Tumor Cells for Enhanced Antitumor Drug Delivery
Some specific types of tumor cells
and tumor endothelial cells
represented CD13 proteins and act as receptors for Asn-Gly-Arg (NGR)
motifs containing peptide. These CD13 receptors can be specifically
recognized and bind through the specific sequence of cyclic NGR (cNGR)
peptide and presented more affinity and specificity toward them. The
cNGR peptide was conjugated to the polyÂ(ethylene glycol) (PEG) terminal
end in the polyÂ(lactic-<i>co</i>-glycolic) acid PLGA-PEG
block copolymer. Then, the ligand conjugated nanoparticles (cNGR-DNB-NPs)
encapsulating docetaxel (DTX) were synthesized from preformed block
copolymer by the emulsion/solvent evaporation method and characterized
for different parameters. The various studies such as <i>in vitro</i> cytotoxicity, cell apoptosis, and cell cycle analysis presented
the enhanced therapeutic potential of cNGR-DNB-NPs. The higher cellular
uptake was also found in cNGR peptide anchored NPs into HUVEC and
HT-1080 cells. However, free cNGR could inhibit receptor mediated
intracellular uptake of NPs into both types of cells at 37 and 4 °C
temperatures, revealing the involvement of receptor-mediated endocytosis.
The <i>in vivo</i> biodistribution and antitumor efficacy
studies indicated that targeted NPs have a higher therapeutic efficacy
through targeting the tumor-specific site. Therefore, the study exhibited
that cNGR-functionalized PEG-PLGA-NPs could be a promising approach
for therapeutic applications to efficient antitumor drug delivery
Design of Novel 3‑Pyrimidinylazaindole CDK2/9 Inhibitors with Potent In Vitro and In Vivo Antitumor Efficacy in a Triple-Negative Breast Cancer Model
In
the present study, a novel series of 3-pyrimidinylazaindoles
were designed and synthesized using a bioinformatics strategy as cyclin-dependent
kinases CDK2 and CDK9 inhibitors, which play critical roles in the
cell cycle control and regulation of cell transcription. The present
approach gives new dimensions to the existing SAR and opens a new
opportunity for the lead optimizations from comparatively inexpensive
starting materials. The study led to the identification of the alternative
lead candidate <b>4ab</b> with a nanomolar potency against CDK2
and CDK9 and potent antiproliferative activities against a panel of
tested tumor cell lines along with a better safety ratio of ∼33
in comparison to reported leads. In addition, the identified lead <b>4ab</b> demonstrated a good solubility and an acceptable in vivo
PK profile. The identified lead <b>4ab</b> showed an in vivo
efficacy in mouse triple-negative breast cancer (TNBC) syngeneic models
with a TGI (tumor growth inhibition) of 90% without any mortality
growth inhibition in comparison to reported leads