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Title: Covalent Guanosine Mimetic Inhibitors of G12C KRAS

Authors:
; ; ; ; ; ; ; ; ; ; ; ORCiD logo
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
INDUSTRYOTHER
OSTI Identifier:
1347801
Resource Type:
Journal Article
Resource Relation:
Journal Name: ACS Medicinal Chemistry Letters; Journal Volume: 8; Journal Issue: 1
Country of Publication:
United States
Language:
ENGLISH

Citation Formats

Xiong, Yuan, Lu, Jia, Hunter, John, Li, Lianbo, Scott, David, Choi, Hwan Geun, Lim, Sang Min, Manandhar, Anuj, Gondi, Sudershan, Sim, Taebo, Westover, Kenneth D., and Gray, Nathanael S.. Covalent Guanosine Mimetic Inhibitors of G12C KRAS. United States: N. p., 2017. Web. doi:10.1021/acsmedchemlett.6b00373.
Xiong, Yuan, Lu, Jia, Hunter, John, Li, Lianbo, Scott, David, Choi, Hwan Geun, Lim, Sang Min, Manandhar, Anuj, Gondi, Sudershan, Sim, Taebo, Westover, Kenneth D., & Gray, Nathanael S.. Covalent Guanosine Mimetic Inhibitors of G12C KRAS. United States. doi:10.1021/acsmedchemlett.6b00373.
Xiong, Yuan, Lu, Jia, Hunter, John, Li, Lianbo, Scott, David, Choi, Hwan Geun, Lim, Sang Min, Manandhar, Anuj, Gondi, Sudershan, Sim, Taebo, Westover, Kenneth D., and Gray, Nathanael S.. Thu . "Covalent Guanosine Mimetic Inhibitors of G12C KRAS". United States. doi:10.1021/acsmedchemlett.6b00373.
@article{osti_1347801,
title = {Covalent Guanosine Mimetic Inhibitors of G12C KRAS},
author = {Xiong, Yuan and Lu, Jia and Hunter, John and Li, Lianbo and Scott, David and Choi, Hwan Geun and Lim, Sang Min and Manandhar, Anuj and Gondi, Sudershan and Sim, Taebo and Westover, Kenneth D. and Gray, Nathanael S.},
abstractNote = {},
doi = {10.1021/acsmedchemlett.6b00373},
journal = {ACS Medicinal Chemistry Letters},
number = 1,
volume = 8,
place = {United States},
year = {Thu Jan 12 00:00:00 EST 2017},
month = {Thu Jan 12 00:00:00 EST 2017}
}
  • Targeted covalent small molecules have shown promise for cancers driven by KRAS G12C. Allosteric compounds that access an inducible pocket formed by movement of a dynamic structural element in KRAS, switch II, have been reported, but these compounds require further optimization to enable their advancement into clinical development. We demonstrate that covalent quinazoline-based switch II pocket (SIIP) compounds effectively suppress GTP loading of KRAS G12C, MAPK phosphorylation, and the growth of cancer cells harboring G12C. Notably we find that adding an amide substituent to the quinazoline scaffold allows additional interactions with KRAS G12C, and remarkably increases the labeling efficiency, potency,more » and selectivity of KRAS G12C inhibitors. Structural studies using X-ray crystallography reveal a new conformation of SIIP and key interactions made by substituents located at the quinazoline 2-, 4-, and 7-positions. Optimized lead compounds in the quinazoline series selectively inhibit KRAS G12C-dependent signaling and cancer cell growth at sub-micromolar concentrations.« less
  • In a prior report it was observed that CTP synthesis and concomitant incorporation of CMP into RNA and dCMP into DNA were markedly reduced in cells cultured in the presence of cycloheximide and puromycin. Experiments described here with Novikoff hepatoma cells reveal that the purine biosynthetic pathway is similarly affected. When the cells are subjected to cycloheximide (30 or 60 ..mu..g/ml) or puromycin (100 ..mu..g/ml), there is a substantial reduction in the bioconversion of hypoxanthine, adenosine, and deoxyadenosine into guanylate compared to untreated cultures. Whereas synthesis (counts per min/nmol) of pool ATP was 70 to 100% of controls, that ofmore » pool GTP was 20 to 35% of controls. Incorporation of AMP into RNA was 40 to 60% of controls, but that of GMP was only 10 to 25% of controls. Incorporation of dAMP into DNA averaged 10% of controls, but that of dGMP was only 4% of controls. Synthesis of guanylates from formate by the de novo pathway was similarly reduced, but incorporation of guanosine, which enters via kinase action alone, was not disproportionately lowered. These results suggest that protein synthesis inhibitors cause a severely reduced availability of newly synthesized GTP and CTP as well as their deoxy counterparts, dGTP and dCTP, the proximal precursors for the synthesis of RNA and DNA. However, the nanomolar levels of all nucleoside triphosphates remain high, probably as a result of recycling of nucleic acid breakdown products. Thus, reduced synthesis of these compounds may restrict nucleic acid synthesis only of some sort of compartmentation leads to a limitation of these precursors at the site(s) of nucleic acid synthesis.« less