Reference Detail

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.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Journal of medicinal chemistry	57	3	2014 Feb 13	903-20	J Med Chem

URL

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