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Ref Type Journal Article
PMID (24387221)
Authors Certal V, Carry JC, Halley F, Virone-Oddos A, Thompson F, Filoche-Rommé B, El-Ahmad Y, Karlsson A, Charrier V, Delorme C, Rak A, Abecassis PY, Amara C, Vincent L, Bonnevaux H, Nicolas JP, Mathieu M, Bertrand T, Marquette JP, Michot N, Benard T, Perrin MA, Lemaitre O, Guerif S, Perron S, Monget S, Gruss-Leleu F, Doerflinger G, Guizani H, Brollo M, Delbarre L, Bertin L, Richepin P, Loyau V, Garcia-Echeverria C, Lengauer C, Schio L
Title Discovery and optimization of pyrimidone indoline amide PI3Kβ inhibitors for the treatment of phosphatase and tensin homologue (PTEN)-deficient cancers.
Abstract Text Compelling molecular biology publications have reported the implication of phosphoinositide kinase PI3Kβ in PTEN-deficient cell line growth and proliferation. These findings supported a scientific rationale for the development of PI3Kβ-specific inhibitors for the treatment of PTEN-deficient cancers. This paper describes the discovery of 2-[2-(2,3-dihydro-indol-1-yl)-2-oxo-ethyl]-6-morpholin-4-yl-3H-pyrimidin-4-one (7) and the optimization of this new series of active and selective pyrimidone indoline amide PI3Kβ inhibitors. 2-[2-(2-Methyl-2,3-dihydro-indol-1-yl)-2-oxo-ethyl]-6-morpholin-4-yl-3H-pyrimidin-4-one (28), identified following a carefully designed methyl scan, displayed improved physicochemical and in vitro pharmacokinetic properties. Structural biology efforts enabled the acquisition of the first X-ray cocrystal structure of p110β with the selective inhibitor compound 28 bound to the ATP site. The nonplanar binding mode described herein is consistent with observed structure-activity relationship for the series. Compound 28 demonstrated significant in vivo activity in a UACC-62 xenograft model in mice, warranting further preclinical investigation. Following successful development, compound 28 entered phase I/Ib clinical trial in patients with advanced cancer.


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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
SAR260301 SAR260301 4 1
Drug Name Trade Name Synonyms Drug Classes Drug Description
SAR260301 SAR 260301|SAR-260301 PIK3CB inhibitor 8 SAR260301 is PI3K beta-selective inhibitor, which has been demonstrated to inhibit tumor growth in xenograft models (PMID: 24387221, PMID: 28976556).
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 dec exp melanoma sensitive SAR260301 Preclinical - Cell line xenograft Actionable In a preclinical study, SAR260301 inhibited tumor growth in xenograft models of melanoma cell lines harboring PTEN deficiency (PMID: 24387221). 24387221