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
  • 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.

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