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

Exploitation of a Novel Binding Pocket in Human Lipoprotein-Associated Phospholipase A2 (Lp-PLA₂) Discovered through X‑ray Fragment Screening

Elevated levels of human lipoprotein-associated phospholipase A2 (Lp-PLA₂) are associated with cardiovascular disease and dementia. A fragment screen was conducted against Lp-PLA₂ 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 Å 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-PLA₂) Discovered through X‑ray Fragment Screening

Elevated levels of human lipoprotein-associated phospholipase A2 (Lp-PLA₂) are associated with cardiovascular disease and dementia. A fragment screen was conducted against Lp-PLA₂ 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 Å 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