[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 (R₃) and back-pocket (R₄) 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 ¹³CNMR measurement of [3-¹³C]­lactate produced from [1,6-¹³C₂]­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 ¹³CNMR measurement of [3-¹³C]­lactate produced from [1,6-¹³C₂]­glucose added to the cell culture