ACS Medicinal Chemistry Letters p. 774 - 779 (2011)
Update date:2022-09-26
Topics:
Burger, Matthew T.
Pecchi, Sabina
Wagman, Allan
Ni, Zhi-Jie
Knapp, Mark
Hendrickson, Thomas
Atallah, Gordana
Pfister, Keith
Zhang, Yanchen
Bartulis, Sarah
Frazier, Kelly
Ng, Simon
Smith, Aaron
Verhagen, Joelle
Haznedar, Joshua
Huh, Kay
Iwanowicz, Ed
Xin, Xiaohua
Menezes, Daniel
Merritt, Hanne
Lee, Isabelle
Wiesmann, Marion
Kaufman, Susan
Crawford, Kenneth
Chin, Michael
Bussiere, Dirksen
Shoemaker, Kevin
Zaror, Isabel
Maira, Sauveur-Michel
Voliva, Charles F.
Phosphoinositide-3-kinases (PI3Ks) are important oncology targets due to the deregulation of this signaling pathway in a wide variety of human cancers. Herein we describe the structure guided optimization of a series of 2-morpholino, 4-substituted, 6-heterocyclic pyrimidines where the pharmacokinetic properties were improved by modulating the electronics of the 6-position heterocycle, and the overall druglike properties were fine-tuned further by modification of the 4-position substituent. The resulting 2,4-bismorpholino 6-heterocyclic pyrimidines are potent class I PI3K inhibitors showing mechanism modulation in PI3K dependent cell lines and in vivo efficacy in tumor xenograft models with PI3K pathway deregulation (A2780 ovarian and U87MG glioma). These efforts culminated in the discovery of 15 (NVP-BKM120), currently in Phase II clinical trials for the treatment of cancer.
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Doi:10.1039/c0cc01487g
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