TY - JOUR
T1 - Discovery and optimization of pyrimidone indoline amide PI3Kβ inhibitors for the treatment of phosphatase and tensin homologue (PTEN)-deficient cancers
AU - Certal, Victor
AU - Carry, Jean Christophe
AU - Halley, Frank
AU - Virone-Oddos, Angela
AU - Thompson, Fabienne
AU - Filoche-Rommé, Bruno
AU - El-Ahmad, Youssef
AU - Karlsson, Andreas
AU - Charrier, Véronique
AU - Delorme, Cécile
AU - Rak, Alexey
AU - Abecassis, Pierre Yves
AU - Amara, Céline
AU - Vincent, Loïc
AU - Bonnevaux, Hélène
AU - Nicolas, Jean Paul
AU - Mathieu, Magali
AU - Bertrand, Thomas
AU - Marquette, Jean Pierre
AU - Michot, Nadine
AU - Benard, Tsiala
AU - Perrin, Marc Antoine
AU - Lemaitre, Olivier
AU - Guerif, Stephane
AU - Perron, Sébastien
AU - Monget, Sylvie
AU - Gruss-Leleu, Florence
AU - Doerflinger, Gilles
AU - Guizani, Houlfa
AU - Brollo, Maurice
AU - Delbarre, Laurence
AU - Bertin, Luc
AU - Richepin, Patrick
AU - Loyau, Véronique
AU - Garcia-Echeverria, Carlos
AU - Lengauer, Christoph
AU - Schio, Laurent
PY - 2014/2/13
Y1 - 2014/2/13
N2 - 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.
AB - 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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U2 - 10.1021/jm401642q
DO - 10.1021/jm401642q
M3 - Article
C2 - 24387221
AN - SCOPUS:84894084021
SN - 0022-2623
VL - 57
SP - 903
EP - 920
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 3
ER -