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Ref Type Journal Article
PMID (25514658)
Authors Barlaam B, Cosulich S, Degorce S, Fitzek M, Green S, Hancox U, Lambert-van der Brempt C, Lohmann JJ, Maudet M, Morgentin R, Pasquet MJ, Péru A, Plé P, Saleh T, Vautier M, Walker M, Ward L, Warin N
Title 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.
Journal Vol Issue Date Pages Journal Short Title
Journal of medicinal chemistry 58 2 2015 Jan 22 943-62 J Med Chem
URL
Abstract Text 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.

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Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
AZD8186 AZD8186 6 1
Drug Name Trade Name Synonyms Drug Classes Drug Description
AZD8186 AZD-8186|AZD 8186 PIK3CB inhibitor 8 PIK3CD inhibitor 27 AZD8186 selectively inhibits the activity of PI3Kbeta (PIK3CB) and delta (PIK3CD) in the PI3K/Akt/mTOR signaling pathway, which may result in decreased tumor cell proliferation (PMID: 25514658, PMID: 32194423).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
PTEN loss prostate cancer sensitive AZD8186 Preclinical Actionable In a preclinical study, AZD8186 inhibited tumor growth of PTEN deficient prostate xenografts models (PMID: 25514658). 25514658