Fragment-Based Approaches to Enhance GTP Competitive KRAS G12C Inhibitors

reportActive / Technical Report | Accession Number: AD1095449 | Open PDF

Abstract:

One of the cancer-causing effects of cigarette smoke is a specific genetic mutation in the KRAS gene, which results in changes in the KRAS protein at codon 12 from glycine to cysteine G12C. KRAS G12C mutations are a major driver of cigarette smoke-associated lung cancers,occurring in 23,000 new cases of lung cancer per year. The Westover lab and collaborators previously developed small molecule inhibitors such as SML-8-73-1 that, in a test tube, irreversibly attach to cysteine 12 and inactivate KRAS G12C protein however, these molecules have poor pharmacological properties. The overall goal of the current project is to improve on these results by developing KRAS G12C inhibitors with pharmacological properties that would allow advancement into preclinical animal models and clinical studies.

Author(s):
Westover, Kenneth
Author Organization(s):
University of Texas Southwestern Medical Center Dallas United States
Descriptive Note:
Technical Report,30 Sep 2017,29 Sep 2018
Pagination:
0030

Security Markings

DOCUMENT & CONTEXTUAL SUMMARY

Distribution:
Approved For Public Release
Distribution Statement:
Approved For Public Release;

RECORD

Collection: TR
Subject Terms
Joint Capability Areas:
JCA_5_Command and Control; JCA_5.3_Planning; JCA_1.2.7_Experimentation; JCA_1.2.5_Lessons Learned; JCA_1.3.2_Personnel Management; JCA_1.2.3_Educating; JCA_1.2.1_Training; JCA_5.5.2_Task; JCA_5.5_Direct
Communities of Interest:
No COI(s) Identified
Descriptor(s):
inhibitors, tobacco smoking, lung cancer, lung cancer, genes, mutations, cysteine, proteins, pharmacology, x ray crystallography
Field(s)/Group(s):
Medicine and Medical Research, Genetic Engineering and Molecular Biology, Pharmacology
Keyword(s):
KRAS gene, small molecule inhibitors, cysteine 12, KRAS G12C protein, guanosine
Report Date:
2018 Oct 01
Creation Date:
2020 Apr 14