4 research outputs found
Protein–Ligand Crystal Structures Can Guide the Design of Selective Inhibitors of the FGFR Tyrosine Kinase
The design of compounds that selectively inhibit a single
kinase
is a significant challenge, particularly for compounds that bind to
the ATP site. We describe here how protein–ligand crystal structure
information was able both to rationalize observed selectivity and
to guide the design of more selective compounds. Inhibition data from
enzyme and cellular screens and the crystal structures of a range
of ligands tested during the process of identifying selective inhibitors
of FGFR provide a step-by-step illustration of the process. Steric
effects were exploited by increasing the size of ligands in specific
regions in such a way as to be tolerated in the primary target and
not in other related kinases. Kinases are an excellent target class
to exploit such approaches because of the conserved fold and small
side chain mobility of the active form
Discovery of a Potent, Selective, and Orally Bioavailable Acidic 11β-Hydroxysteroid Dehydrogenase Type 1 (11β-HSD1) Inhibitor: Discovery of 2-[(3<i>S</i>)-1-[5-(Cyclohexylcarbamoyl)-6-propylsulfanylpyridin-2-yl]-3-piperidyl]acetic Acid (AZD4017)
Inhibition of 11β-HSD1 is an attractive mechanism
for the
treatment of obesity and other elements of the metabolic syndrome.
We report here the discovery of a nicotinic amide derived carboxylic
acid class of inhibitors that has good potency, selectivity, and pharmacokinetic
characteristics. Compound <b>11i</b> (AZD4017) is an effective
inhibitor of 11β-HSD1 in human adipocytes and exhibits good
druglike properties and as a consequence was selected for clinical
development
Pyrimidinone Nicotinamide Mimetics as Selective Tankyrase and Wnt Pathway Inhibitors Suitable for in Vivo Pharmacology
The canonical Wnt pathway plays an
important role in embryonic
development, adult tissue homeostasis, and cancer. Germline mutations
of several Wnt pathway components, such as Axin, APC, and Ăź-catenin,
can lead to oncogenesis. Inhibition of the polyÂ(ADP-ribose) polymerase
(PARP) catalytic domain of the tankyrases (TNKS1 and TNKS2) is known
to inhibit the Wnt pathway via increased stabilization of Axin. In
order to explore the consequences of tankyrase and Wnt pathway inhibition
in preclinical models of cancer and its impact on normal tissue, we
sought a small molecule inhibitor of TNKS1/2 with suitable physicochemical
properties and pharmacokinetics for hypothesis testing in vivo. Starting
from a 2-phenyl quinazolinone hit (compound <b>1</b>), we discovered
the pyrrolopyrimidinone compound <b>25</b> (AZ6102), which is
a potent TNKS1/2 inhibitor that has 100-fold selectivity against other
PARP family enzymes and shows 5 nM Wnt pathway inhibition in DLD-1
cells. Moreover, compound <b>25</b> can be formulated well in
a clinically relevant intravenous solution at 20 mg/mL, has demonstrated
good pharmacokinetics in preclinical species, and shows low Caco2
efflux to avoid possible tumor resistance mechanisms
Thiazolopyridine Ureas as Novel Antitubercular Agents Acting through Inhibition of DNA Gyrase B
A pharmacophore-based search led
to the identification of thiazolopyridine
ureas as a novel scaffold with antitubercular activity acting through
inhibition of DNA Gyrase B (GyrB) ATPase. Evaluation of the binding
mode of thiazolopyridines in a Mycobacterium tuberculosis (Mtb) GyrB homology model prompted exploration of the side chains
at the thiazolopyridine ring C-5 position to access the ribose/solvent
pocket. Potent compounds with GyrB IC<sub>50</sub> ≤ 1 nM and
Mtb MIC ≤ 0.1 μM were obtained with certain combinations
of side chains at the C-5 position and heterocycles at the C-6 position
of the thiazolopyridine core. Substitutions at C-5 also enabled optimization
of the physicochemical properties. Representative compounds were cocrystallized
with Streptococcus pneumoniae (Spn)
ParE; these confirmed the binding modes predicted by the homology
model. The target link to GyrB was confirmed by genetic mapping of
the mutations conferring resistance to thiazolopyridine ureas. The
compounds are bactericidal in vitro and efficacious in vivo in an
acute murine model of tuberculosis