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Drugging an undruggable pocket on KRAS

Journal Article · · Proceedings of the National Academy of Sciences of the United States of America
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  1. Boehringer Ingelheim Regional Center Vienna GmbH & Co KG (Austria)
  2. Vanderbilt Univ. School of Medicine, Nashville, TN (United States)
  3. Boehringer Ingelheim Pharma GmbH & Co KG (Germany)
  4. Vanderbilt Univ. School of Medicine, Nashville, TN (United States); Vanderbilt Univ., Nashville, TN (United States)
+ Show Author Affiliations
The 3 human RAS genes, KRAS, NRAS, and HRAS, encode 4 different RAS proteins which belong to the protein family of small GTPases that function as binary molecular switches involved in cell signaling. Activating mutations in RAS are among the most common oncogenic drivers in human cancers, with KRAS being the most frequently mutated oncogene. Although KRAS is an excellent drug discovery target for many cancers, and despite decades of research, no therapeutic agent directly targeting RAS has been clinically approved. Using structure-based drug design, we have discovered BI-2852 (1), a KRAS inhibitor that binds with nanomolar affinity to a pocket, thus far perceived to be “undruggable,” between switch I and II on RAS; 1 is mechanistically distinct from covalent KRASG12C inhibitors because it binds to a different pocket present in both the active and inactive forms of KRAS. In doing so, it blocks all GEF, GAP, and effector interactions with KRAS, leading to inhibition of downstream signaling and an antiproliferative effect in the low micromolar range in KRAS mutant cells. These findings clearly demonstrate that this so-called switch I/II pocket is indeed druggable and provide the scientific community with a chemical probe that simultaneously targets the active and inactive forms of KRAS
Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Organization:
National Institutes of Health (NIH); National Cancer Institute (NCI); Lustgarten Foundation for Pancreatic Cancer Research; Austrian Forschungsförderungsgesellschaft (FFG); USDOE Office of Science (SC)
Grant/Contract Number:
AC02-06CH11357
OSTI ID:
1593440
Journal Information:
Proceedings of the National Academy of Sciences of the United States of America, Journal Name: Proceedings of the National Academy of Sciences of the United States of America Journal Issue: 32 Vol. 116; ISSN 0027-8424
Publisher:
National Academy of SciencesCopyright Statement
Country of Publication:
United States
Language:
ENGLISH

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Cited By (14)

The current understanding of KRAS protein structure and dynamics journal January 2020
A potent KRAS macromolecule degrader specifically targeting tumours with mutant KRAS journal June 2020
The small molecule BI-2852 induces a nonfunctional dimer of KRAS journal February 2020
Reply to Tran et al.: Dimeric KRAS protein–protein interaction stabilizers journal February 2020
RAS Nanoclusters: Dynamic Signaling Platforms Amenable to Therapeutic Intervention journal March 2021
Insights into Structures and Dynamics of Flavivirus Proteases from NMR Studies journal April 2020
Defining and Targeting Adaptations to Oncogenic KRASG12C Inhibition Using Quantitative Temporal Proteomics journal March 2020
Inhibition of K-Ras4B-plasma membrane association with a membrane microdomain-targeting peptide journal January 2020
Therapeutic targeting of protein S-acylation for the treatment of disease journal December 2019
Therapeutic target database 2020: enriched resource for facilitating research and early development of targeted therapeutics journal November 2019
Development of a cell-free split-luciferase biochemical assay as a tool for screening for inhibitors of challenging protein-protein interaction targets journal January 2020
Development of a cell-free split-luciferase biochemical assay as a tool for screening for inhibitors of challenging protein-protein interaction targets journal January 2020
Targeting Endogenous K-RAS for Degradation Through the Affinity-Directed Protein Missile System journal January 2019
Exploiting RAS Nucleotide Cycling as a Strategy for Drugging RAS-Driven Cancers journal December 2019

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Related Subjects

60 APPLIED LIFE SCIENCES
KRAS
NMR
fragment-based drug design
oncology
structure-based drug design