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

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

  • J Med Chem. 2014 Feb 13;57(3):903-20. doi: 10.1021/jm401642q.
Victor Certal 1,  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 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
Affiliations

Affiliation

  • 1 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.
PMID: 24387221 DOI: 10.1021/jm401642q
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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-15837
    99.95%, PI3Kβ Inhibitor