Discovery and Optimization of Pyrimidone Indoline Amide PI3Kβ Inhibitors for the Treatment of Phosphatase and Tensin Homologue (PTEN)-Deficient Cancers

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• 作者：Victor Certal ; Jean-Christophe Carry ; Frank Halley ; Angela Virone-Oddos ; Fabienne Thompson ; Bruno Filoche-Rommé ; Youssef El-Ahmad ; Andreas Karlsson ; Véronique Charrier ; Cécile Delorme ; Alexey Rak ; Pierre-Yves Abecassis ; Céline Amara ; Lo?c Vincent ; Hélène Bonnevaux ; Jean-Paul Nicolas ; Magali Mathieu ; Thomas Bertrand ; Jean-Pierre Marquette ; Nadine Michot ; Tsiala Benard ; Marc-Antoine Perrin ; Olivier Lemaitre ; Stephane Guerif ; Sébastien Perron ; Sylvie Monget ; Florence Gruss-Leleu ; Gilles Doerflinger ; Houlfa Guizani ; Maurice Brollo ; Laurence Delbarre ; Luc Bertin ; Patrick Richepin ; Véronique Loyau ; Carlos Garcia-Echeverria ; Christoph Lengauer ; Laurent Schio
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：February 13, 2014
• 年：2014
• 卷：57
• 期：3
• 页码：903-920
• 全文大小：771K
• ISSN：1520-4804

文摘

Compelling molecular biology publications have reported the implication of phosphoinositide kinase PI3K尾 in PTEN-deficient cell line growth and proliferation. These findings supported a scientific rationale for the development of PI3K尾-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 PI3K尾 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 p110尾 with the selective inhibitor compound 28 bound to the ATP site. The nonplanar binding mode described herein is consistent with observed structure鈥揳ctivity 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.