[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

Discovery of a Potent Class of PI3Kα Inhibitors with Unique Binding Mode via Encoded Library Technology (ELT)

In the search of PI3K p110α wild type and H1047R mutant selective small molecule leads, an encoded library technology (ELT) campaign against the desired target proteins was performed which led to the discovery of a selective chemotype for PI3K isoforms from a three-cycle DNA encoded library. An X-ray crystal structure of a representative inhibitor from this chemotype demonstrated a unique binding mode in the p110α protein

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