4 research outputs found
[3<i>a</i>,4]-Dihydropyrazolo[1,5<i>a</i>]pyrimidines: Novel, Potent, and Selective Phosphatidylinositol-3-kinase β Inhibitors
A series of novel [3<i>a</i>,4]dihydropyrazolo[1,5<i>a</i>]pyrimidines were identified, which were highly potent
and selective inhibitors of PI3Kβ. The template afforded the
opportunity to develop novel SAR for both the hinge-binding (R<sub>3</sub>) and back-pocket (R<sub>4</sub>) substitutents. While cellular
potency was relatively modest due to high protein binding, the series
displayed low clearance in rat, mouse, and monkey
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]lactate produced from
[1,6-<sup>13</sup>C<sub>2</sub>]glucose 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]lactate produced from
[1,6-<sup>13</sup>C<sub>2</sub>]glucose added to the cell culture