4BFR

Discovery and Optimization of Pyrimidone Indoline Amide PI3Kbeta Inhibitors for the Treatment of Phosphatase and TENsin homologue (PTEN)-Deficient Cancers

Summary for 4BFR

• Entry DOI: 10.2210/pdb4bfr/pdb
• Descriptor: PHOSPHATIDYLINOSITOL 4,5-BISPHOSPHATE 3-KINASE CATALYTIC S SUBUNIT BETA ISOFORM, 2-[2-(2-METHYL-2,3-DIHYDRO-INDOL-1-YL)-2-OXO-ETHYL]-6-MORPHOLIN-4-YL-3H-PYRIMIDIN-4-ONE (3 entities in total)
• Functional Keywords: transferase, inhibitor
• Biological source: MUS MUSCULUS (HOUSE MOUSE)
• Total number of polymer chains: 2
• Total formula weight: 218708.29

Authors

Certal, V.,Carry, J.C.,Halley, F.,Virone-Oddos, A.,Thompson, F.,Filoche-Romme, B.,El-Ahmad, Y.,Karlsson, A.,Charrier, V.,Delorme, C.,Rak, A.,Abecassis, P.Y.,Amara, C.,Vincent, L.,Bonnevaux, H.,Nicolas, J.P.,Mathieu, M.,Bertrand, T.,Marquette, J.P.,Michot, N.,Benard, T.,Perrin, M.A.,Perron, S.,Monget, S.,Gruss-Leleu, F.,Doerflinger, G.,Guizani, H.,Brollo, M.,Delbarre, L.,Bertin, L.,Richepin, P.,Loyau, V.,Garcia-Echeverria, C.,Lengauer, C.,Schio, L. (deposition date: 2013-03-22, release date: 2014-01-15, Last modification date: 2023-12-20)

Primary citation

Certal, V.,Carry, J.B.,Halley, F.,Virone-Oddos, A.,Thompson, F.,Filoche-Romme, B.,El-Ahmad, Y.,Karlsson, A.,Charrier, V.,Delorme, C.,Rak, A.,Abecassis, P.,Amara, C.,Vincent, L.,Bonnevaux, H.,Nicolas, J.,Mathieu, M.,Bertrand, T.,Marquette, J.,Michot, N.,Benard, T.,Perrin, M.,Lemaitre, O.,Guerif, S.,Perron, S.,Monget, S.,Gruss-Leleu, F.,Doerflinger, G.,Guizani, H.,Brollo, M.,Delbarre, L.,Bertin, L.,Richepin, P.,Loyau, V.,Garcia-Echeverria, C.,Lengauer, C.,Schio, L.
Discovery and Optimization of Pyrimidone Indoline Amide Pi3Kbeta Inhibitors for the Treatment of Phosphatase and Tensin Homologue (Pten)-Deficient Cancers.
J.Med.Chem., 57:903-, 2014

PubMed 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.

PubMed: 24387221
DOI: 10.1021/JM401642Q

Experimental method

X-RAY DIFFRACTION (2.8 Å)