6n3l | pdb_00006n3l
Identification of novel, potent and selective GCN2 inhibitors as first-in-class anti-tumor agents
Structural highlights
Disease[E2AK4_HUMAN] Pulmonary venoocclusive disease;Pulmonary capillary hemangiomatosis;Heritable pulmonary arterial hypertension. The disease is caused by mutations affecting the gene represented in this entry. Function[E2AK4_HUMAN] Metabolic-stress sensing protein kinase that phosphorylates the alpha subunit of eukaryotic translation initiation factor 2 (eIF-2-alpha/EIF2S1) on 'Ser-52' in response to low amino acid availability (PubMed:25329545). Plays a role as an activator of the integrated stress response (ISR) required for adapatation to amino acid starvation. Converts phosphorylated eIF-2-alpha/EIF2S1 either to a competitive inhibitor of the translation initiation factor eIF-2B, leading to a global protein synthesis repression, and thus to a reduced overall utilization of amino acids, or to a translational initiation activation of specific mRNAs, such as the transcriptional activator ATF4, and hence allowing ATF4-mediated reprogramming of amino acid biosynthetic gene expression to alleviate nutrient depletion. Binds uncharged tRNAs (By similarity). Involved in cell cycle arrest by promoting cyclin D1 mRNA translation repression after the unfolded protein response pathway (UPR) activation or cell cycle inhibitor CDKN1A/p21 mRNA translation activation in response to amino acid deprivation (PubMed:26102367). Plays a role in the consolidation of synaptic plasticity, learning as well as formation of long-term memory. Plays a role in neurite outgrowth inhibition. Plays a proapoptotic role in response to glucose deprivation. Promotes global cellular protein synthesis repression in response to UV irradiation independently of the stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) and p38 MAPK signaling pathways (By similarity). Plays a role in the antiviral response against alphavirus infection; impairs early viral mRNA translation of the incoming genomic virus RNA, thus preventing alphavirus replication (By similarity).[UniProtKB:P15442][UniProtKB:Q9QZ05][1] [2] (Microbial infection) Plays a role in modulating the adaptive immune response to yellow fever virus infection; promotes dendritic cells to initiate autophagy and antigene presentation to both CD4(+) and CD8(+) T-cells under amino acid starvation (PubMed:24310610).[3] Publication Abstract from PubMedGeneral 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 alphaC-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. Identification of Novel, Potent, and Orally Available GCN2 Inhibitors with Type I Half Binding Mode.,Fujimoto J, Kurasawa O, Takagi T, Liu X, Banno H, Kojima T, Asano Y, Nakamura A, Nambu T, Hata A, Ishii T, Sameshima T, Debori Y, Miyamoto M, Klein MG, Tjhen R, Sang BC, Levin I, Lane SW, Snell GP, Li K, Kefala G, Hoffman ID, Ding SC, Cary DR, Mizojiri R ACS Med Chem Lett. 2019 Sep 19;10(10):1498-1503. doi:, 10.1021/acsmedchemlett.9b00400. eCollection 2019 Oct 10. PMID:31620240[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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