Open AccessIdentification of Novel, Potent, and Orally Available GCN2 Inhibitors with Type I Half Binding Mode
Author(s) -
Jun Fujimoto,
Osamu Kurasawa,
Terufumi Takagi,
Xin Liu,
Hiroshi Banno,
Takuto Kojima,
Yasutomi Asano,
Akira Nakamura,
Tadahiro Nambu,
Akito Hata,
Tsuyoshi Ishii,
Tomoya Sameshima,
Yasuyuki Debori,
Maki Miyamoto,
Michael G. Klein,
Richard Tjhen,
BiChing Sang,
Irena Levin,
Scott Weston Lane,
G. Snell,
Ké Li,
Georgia Kefala,
Isaac Hoffman,
Sheng Ding,
Douglas R. Cary,
Ryo Mizojiri
Publication year - 2019
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/acsmedchemlett.9b00400
Subject(s) - chemistry , asparagine , allosteric regulation , kinase , cell culture , pharmacology , potency , biochemistry , amino acid , cancer research , enzyme , biology , in vitro , genetics
General control nonderepressible 2 (GCN2) is a master regulator kinase of amino acid homeostasis and important for cancer survival in the tumor microenvironment under amino acid depletion. We initiated studies aiming at the discovery of novel GCN2 inhibitors as first-in-class antitumor agents and conducted modification of the substructure of sulfonamide derivatives with expected type I half binding on GCN2. Our synthetic strategy mainly corresponding to the αC-helix allosteric pocket of GCN2 led to significant enhancement in potency and a good pharmacokinetic profile in mice. In addition, compound 6d , which showed slow dissociation in binding on GCN2, demonstrated antiproliferative activity in combination with the asparagine-depleting agent asparaginase in an acute lymphoblastic leukemia (ALL) cell line, and it also displayed suppression of GCN2 pathway activation with asparaginase treatment in the ALL cell line and mouse xenograft model.