5 research outputs found
Rational Design, Synthesis, and SAR of a Novel Thiazolopyrimidinone Series of Selective PI3K-beta Inhibitors
A novel thiazolopyrimidinone series of PI3K-beta selective inhibitors
has been identified. This chemotype has provided an excellent tool
compound, <b>18</b>, that showed potent growth inhibition in
the PTEN-deficient breast cancer cell line MDA-MB-468 under anchorage-independent
conditions, and it also demonstrated pharmacodynamic effects and efficacy
in a PTEN-deficient prostate cancer PC-3 xenograft mouse model
Discovery of a Novel 2,6-Disubstituted Glucosamine Series of Potent and Selective Hexokinase 2 Inhibitors
A novel series of potent and selective
hexokinase 2 (HK2) inhibitors,
2,6-disubstituted glucosamines, has been identified based on HTS hits,
exemplified by compound <b>1</b>. Inhibitor-bound crystal structures
revealed that the HK2 enzyme could adopt an “induced-fit”
conformation. The SAR study led to the identification of potent HK2
inhibitors, such as compound <b>34</b> with greater than 100-fold
selectivity over HK1. Compound <b>25</b> inhibits <i>in
situ</i> glycolysis in a UM-UC-3 bladder tumor cell line via <sup>13</sup>CNMR measurement of [3-<sup>13</sup>C]Âlactate produced from
[1,6-<sup>13</sup>C<sub>2</sub>]Âglucose added to the cell culture
Discovery of a Novel 2,6-Disubstituted Glucosamine Series of Potent and Selective Hexokinase 2 Inhibitors
A novel series of potent and selective
hexokinase 2 (HK2) inhibitors,
2,6-disubstituted glucosamines, has been identified based on HTS hits,
exemplified by compound <b>1</b>. Inhibitor-bound crystal structures
revealed that the HK2 enzyme could adopt an “induced-fit”
conformation. The SAR study led to the identification of potent HK2
inhibitors, such as compound <b>34</b> with greater than 100-fold
selectivity over HK1. Compound <b>25</b> inhibits <i>in
situ</i> glycolysis in a UM-UC-3 bladder tumor cell line via <sup>13</sup>CNMR measurement of [3-<sup>13</sup>C]Âlactate produced from
[1,6-<sup>13</sup>C<sub>2</sub>]Âglucose added to the cell culture
Exploitation of a Novel Binding Pocket in Human Lipoprotein-Associated Phospholipase A2 (Lp-PLA<sub>2</sub>) Discovered through X‑ray Fragment Screening
Elevated levels of
human lipoprotein-associated phospholipase A2
(Lp-PLA<sub>2</sub>) are associated with cardiovascular disease and
dementia. A fragment screen was conducted against Lp-PLA<sub>2</sub> in order to identify novel inhibitors. Multiple fragment hits were
observed in different regions of the active site, including some hits
that bound in a pocket created by movement of a protein side chain
(approximately 13 Ă… from the catalytic residue Ser273). Using
structure guided design, we optimized a fragment that bound in this
pocket to generate a novel low nanomolar chemotype, which did not
interact with the catalytic residues
Exploitation of a Novel Binding Pocket in Human Lipoprotein-Associated Phospholipase A2 (Lp-PLA<sub>2</sub>) Discovered through X‑ray Fragment Screening
Elevated levels of
human lipoprotein-associated phospholipase A2
(Lp-PLA<sub>2</sub>) are associated with cardiovascular disease and
dementia. A fragment screen was conducted against Lp-PLA<sub>2</sub> in order to identify novel inhibitors. Multiple fragment hits were
observed in different regions of the active site, including some hits
that bound in a pocket created by movement of a protein side chain
(approximately 13 Ă… from the catalytic residue Ser273). Using
structure guided design, we optimized a fragment that bound in this
pocket to generate a novel low nanomolar chemotype, which did not
interact with the catalytic residues