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|Ref Type||Journal Article|
|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||Journal of medicinal chemistry|
|Date||2015 Jan 22|
|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.|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|AZD8186||AZD-8186|AZD 8186||PIK3CB inhibitor 8 PIK3CD inhibitor 26||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|