Georges Pasquet

Synthesis and SAR of 1-acetanilide-4-aminopyrazole-substituted quinazolines: Selective inhibitors of Aurora B kinase with potent anti-tumor activity

A new class of 1-acetanilide-4-aminopyrazole-substituted quinazoline Aurora kinase inhibitors has been discovered possessing highly potent cellular activity. Continuous infusion into athymic mice bearing SW620 tumors of the soluble phosphate derivative 2 led to dose-proportional exposure of the des-phosphate compound 8 with a high-unbound fraction. The combination of potent cell activity and high free-drug exposure led to pharmacodynamic changes in the tumor at low doses, indicative of Aurora B-kinase inhibition and a reduction in tumor volume.

Discovery of AZD2932, a new Quinazoline Ether Inhibitor with high affinity for VEGFR-2 and PDGFR tyrosine kinases.

A new series of Quinazoline Ether Inhibitor which potently inhibits VEGFR-2 and PDGFR tyrosine kinases is described here. In vitro, pharmacokinetics and in vivo evaluations led to the selection of AZD2932.

Synthesis of (±)-negamycin and of (±)-epinegamycin

Abstract The antibiotic negamycin and its diastereomer have both been synthesized in racemic form. The latter has been found to possess antibacterial activity, but at a lower level than negamycin itself.

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

Starting from potent inhibitors of PI3Kα having poor general kinase selectivity (e.g., 1 and 2), optimisation of this series led to the identification of 25, a potent inhibitor of PI3Kα (wild type, E545K and H1047R mutations) and PI3Kδ, selective versus PI3Kβ and PI3Kγ, with excellent general kinase selectivity. Compound 25 displayed low metabolic turnover and suitable physical properties for oral administration. In vivo, compound 25 showed pharmacodynamic modulation of AKT phosphorylation and near complete inhibition of tumour growth (93% tumour growth inhibition) in a murine H1047R PI3Kα mutated SKOV-3 xenograft tumour model after chronic oral administration at 25mg/kg b.i.d. Compound 25, also known as AZD8835, is currently in phase I clinical trials.

Discovery of new quinoline ether inhibitors with high affinity and selectivity for PDGFR tyrosine kinases.

A new series of quinoline ether inhibitors, which potently and selectively inhibit PDGFR tyrosine kinases, is described in this Letter. Compounds 23 and 33 are selective, low nanomolar inhibitors of PDGFRα and β, display good pharmacokinetics in rat and dog and are active in vivo at low doses when given orally twice daily. Further evaluation of these compounds is warranted.

Abstract 2830: Discovery of AZD8835, a potent and selective inhibitor of PI3Kα and PI3Kδ for the treatment of PIK3CA-dependent cancers

Amplification and mutations of the PIK3CA gene encoding the p110α catalytic unit of PI3Kα occur frequently in many human cancers including ca. 25% of breast cancers. The three most common mutations (E542K, E545K and H1047R) in the PIK3CA gene have been confirmed as activating mutations. The strong evidence pointing at the oncogenic nature of the PIK3CA gene mutations and their high frequency have fuelled a strong interest in developing selective inhibitors of PI3Kα. During the lead generation phase of this project, we identified a series of 2-amino pyridines / pyrazines as potent inhibitors of PI3Kα both at the enzymatic and the cellular level. However, these initial leads displayed poor general kinase selectivity. We report the optimisation of this series, with a special focus on optimisation of general kinase selectivity. This work led to the identification of AZD8835, a potent inhibitor of PI3Kα (wild type, E545K and H1047R mutations) and PI3Kδ with excellent selectivity vs. PI3Kβ, PI3Kγ and an excellent general kinase selectivity. AZD8835 is a potent inhibitor of p-Akt in cells sensitive to PI3Kα inhibition (IC50 0.057 μM in PIK3CA mutant human breast ductal carcinoma BT474 cell line) and in cells sensitive to PI3Kδ inhibition (IC50 0.049 μM in JeKo-1 B cell line), but not to cells sensitive to PI3Kβ inhibition (IC50 3.5 μM in PTEN null breast adenocarcinoma MDA-MB-468 cell line) or PI3Kγ inhibition (IC50 0.53 μM in monocytic RAW264 cell line). Furthermore, AZD8835 displayed high metabolic stability and suitable physical properties for oral administration. In vivo, inhibition of p-Akt was observed at 30 minutes and 8 hours in the PIK3CA H1047R mutant SKOV3 tumour model in mice after chronic oral administration of AZD8835 (25 mg/kg b.i.d.). AZD8835 showed excellent tumour growth inhibition in this same model after chronic oral administration (25 mg/kg b.i.d.). Based on these results, AZD8835 was selected as a clinical candidate for the treatment of PIK3CA-dependant cancers and has recently entered phase I clinical trials. Citation Format: Bernard Barlaam, Sabina Cosulich, Benedicte Delouvrie, Martina Fitzek, Herve Germain, Stephen Green, Craig S. Harris, Kevin Hudson, Christine Lambert-van der Brempt, Maryannick Lamorlette, Le Griffon Antoine, Remy Morgentin, Gilles Ouvry, Ken Page, Georges Pasquet, Linette Ruston, Twana Saleh, Michel Vautier, Lara Ward. Discovery of AZD8835, a potent and selective inhibitor of PI3Kα and PI3Kδ for the treatment of PIK3CA-dependent cancers. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2830. doi:10.1158/1538-7445.AM2015-2830