Discovery and optimization of pyrimidone indoline amide PI3Kβ inhibitors for the treatment of phosphatase and tensin homologue (PTEN)-deficient cancers

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, Loïc Vincent, Hélène Bonnevaux, Jean Paul Nicolas, Magali Mathieu, Thomas Bertrand, Jean Pierre Marquette, Nadine MichotTsiala 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

Research output: Contribution to journalArticlepeer-review

56 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)903-920
Number of pages18
JournalJournal of Medicinal Chemistry
Issue number3
StatePublished - Feb 13 2014
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery


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