title: Discovery and optimization of pyrimidone indoline amide PI3Kβ inhibitors for the treatment of phosphatase and tensin homologue (PTEN)-deficient cancers.
abstract: 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.
authors.affiliation: Oncology Drug Discovery, §Structure Design Informatics, and Structural Biology, #Drug Disposition and Safety (DSAR), †Protein Production,⊥Pharmaceutical Sciences, ∥Analytical Sciences, Sanofi , 13, quai Jules Guesde, 94403 Vitry-sur-Seine, France.
authors.forename: Victor
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authors.lastname: Certal
authors.forename: Jean-Christophe
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authors.forename: Frank
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authors.lastname: Virone-Oddos
authors.forename: Fabienne
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authors.forename: Youssef
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authors.forename: Véronique
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authors.forename: Pierre-Yves
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authors.forename: Céline
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authors.lastname: Amara
authors.forename: Loïc
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authors.forename: Hélène
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authors.lastname: Nicolas
authors.forename: Magali
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authors.lastname: Mathieu
authors.forename: Thomas
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authors.lastname: Bertrand
authors.forename: Jean-Pierre
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authors.lastname: Marquette
authors.forename: Nadine
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authors.lastname: Michot
authors.forename: Tsiala
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authors.lastname: Benard
authors.forename: Marc-Antoine
authors.initials: MA
authors.lastname: Perrin
authors.forename: Olivier
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authors.lastname: Lemaitre
authors.forename: Stephane
authors.initials: S
authors.lastname: Guerif
authors.forename: Sébastien
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authors.lastname: Perron
authors.forename: Sylvie
authors.initials: S
authors.lastname: Monget
authors.forename: Florence
authors.initials: F
authors.lastname: Gruss-Leleu
authors.forename: Gilles
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authors.lastname: Doerflinger
authors.forename: Houlfa
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authors.lastname: Guizani
authors.forename: Maurice
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authors.lastname: Brollo
authors.forename: Laurence
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authors.lastname: Delbarre
authors.forename: Luc
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authors.lastname: Bertin
authors.forename: Patrick
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authors.lastname: Richepin
authors.forename: Véronique
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authors.lastname: Loyau
authors.forename: Carlos
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authors.lastname: Garcia-Echeverria
authors.forename: Christoph
authors.initials: C
authors.lastname: Lengauer
authors.forename: Laurent
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authors.lastname: Schio
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D001682:Biological Availability; D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability; D018360:Crystallography, X-Ray; D004285:Dogs; D004354:Drug Screening Assays, Antitumor; D005260:Female; D064593:Heterografts; D006801:Humans; D007211:Indoles / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D008862:Microsomes, Liver / Q000378:metabolism; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D051059:PTEN Phosphohydrolase / Q000172:deficiency* / Q000235:genetics; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011485:Protein Binding; D011744:Pyrimidinones / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D011923:Rats, Nude; D012995:Solubility; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: C587727:2-(2-(2-methyl-2,3-dihydroindol-1-yl)-2-oxoethyl)-6-morpholin-4-yl-3H-pyrimidin-4-one; D000970:Antineoplastic Agents; D007211:Indoles; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011744:Pyrimidinones; D051059:PTEN Phosphohydrolase