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: 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 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
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 57 Issue 3 Pg. 903-20 (Feb 13 2014) ISSN: 1520-4804 [Electronic] United States
• PMID: 24387221 (Publication Type: Journal Article)

Chemical References

• 2-(2-(2-methyl-2,3-dihydroindol-1-yl)-2-oxoethyl)-6-morpholin-4-yl-3H-pyrimidin-4-one
• Antineoplastic Agents
• Indoles
• Phosphoinositide-3 Kinase Inhibitors
• Pyrimidinones
• PTEN Phosphohydrolase

Topics

• Animals
• Antineoplastic Agents (chemistry, pharmacokinetics, pharmacology)
• Biological Availability
• Cell Line, Tumor
• Cell Membrane Permeability
• Crystallography, X-Ray
• Dogs
• Drug Screening Assays, Antitumor
• Female
• Heterografts
• Humans
• Indoles (chemistry, pharmacokinetics, pharmacology)
• Male
• Mice
• Mice, Inbred BALB C
• Mice, SCID
• Microsomes, Liver (metabolism)
• Molecular Conformation
• Molecular Docking Simulation
• Neoplasm Transplantation
• Neoplasms (drug therapy, enzymology)
• PTEN Phosphohydrolase (deficiency, genetics)
• Phosphoinositide-3 Kinase Inhibitors
• Protein Binding
• Pyrimidinones (chemistry, pharmacokinetics, pharmacology)
• Rats
• Rats, Nude
• Solubility
• Stereoisomerism
• Structure-Activity Relationship