Discovery of (R)-8-(1-(3,5-Difluorophenylamino)ethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (AZD8186): A Potent and Selective Inhibitor of PI3Kβ and PI3Kδ for the Treatment of PTEN-Deficient Cancers

Abstract

Several studies have highlighted the dependency of PTEN deficient tumors to PI3Kβ activity and specific inhibition of PI3Kδ has been shown activity against human B-cell cancers. We describe the discovery and optimization of a series of 8-(1-anilino)ethyl)-2-morpholino-4-oxo-4H-chromene-6-carboxamides as PI3Kβ/δ inhibitors, which led to the discovery of the clinical candidate 13, also known as AZD8186. On the basis of the lower lipophilicity of the chromen-4-one core compared to the previously utilized pyrido[1,2-a]pyrimid-4-one core, this series of compounds displayed high metabolic stability and suitable physical properties for oral administration. Compound 13 showed profound pharmacodynamic modulation of p-Akt in PTEN-deficient PC3 prostate tumor bearing mice after oral administration and showed complete inhibition of tumor growth in the mouse PTEN-deficient PC3 prostate tumor xenograft model. 13 was selected as a clinical candidate for treatment of PTEN-deficient cancers and has recently entered phase I clinical trials.

Inhibition of cholesterol metabolism underlies synergy between mTOR pathway inhibition and chloroquine in bladder cancer cells

“…We therefore used a selection of highly selective and potent kinase inhibitors targeting relevant genetic aberrations along these pathways in bladder cancer cell lines: FGFRi (AZD4547), PI3Kβ/δi (AZD8186), AKTi (AZD5363) and mTORi (AZD2014); and assayed cell death over 5 days. 22, 23, 24, 25 Data relating to RT112, which express constitutively active FGFR3 (FGFR3-TACC3), are shown in Figure 1 and used throughout this study to represent our major findings. 26 RT112 cultures showed marked sensitivity to both FGFRi and mTORi, but tolerated AKTi and PI3Kβi (Figure 1a).…”

In vitro and in vivo model systems used in prostate cancer research

“…This has led some investigators to speculate that this is one factor that makes bone a hospitable metastatic site. It expresses aberrant p53 with a C deletion in codon 138 causing a nonsense codon at 169 (causing a loss of heterozygosity) and is PTEN deficient [42,43]. Little information is available on xenograft growth rates, but our experience with intratibial cancer cell inoculations suggests it is similar to DU-145 cells with latency of approximately one week and doubling times in the range of 4–5 days.…”

Discovery of 1-(4-(5-(5-amino-6-(5-tert-butyl-1,3,4-oxadiazol-2-yl)pyrazin-2-yl)-1-ethyl-1,2,4-triazol-3-yl)piperidin-1-yl)-3-hydroxypropan-1-one (AZD8835): A potent and selective inhibitor of PI3Kα and PI3Kδ for the treatment of cancers

“…Selectivity across the PI3K isoforms was routinely measured with biochemical enzyme assays and the  selectivity was also monitored in cell assays (inhibition of AKT phosphorylation at Thr308 in PIK3CA mutant human breast ductal carcinoma BT474 cells, sensitive to PI3Kinhibition, and at Ser473 in PTEN-null breast adenocarcinoma MDA-MB-468 cells, sensitive to PI3Kinhibition; providing measurements of PI3K and PI3Kinhibition respectively. 23 Kinase promiscuity was routinely measured using several kinase enzyme assays: KDR, Aurora B, FGFR1, GSK3, but for simplicity, only the KDR and/or FGFR1 enzyme results are reported in this paper. Broader kinase selectivity was confirmed for prioritized compound(s) using additional panel screens.…”