Asset Details
Do you wish to reserve the book?
Anti-tumor efficacy of a potent and selective non-covalent KRASG12D inhibitor
Hey, we have placed the reservation for you!
By the way, why not check out events that you can attend while you pick your title.
Oops! Something went wrong.
Looks like we were not able to place the reservation. Kindly try again later.
Are you sure you want to remove the book from the shelf?
Anti-tumor efficacy of a potent and selective non-covalent KRASG12D inhibitor
Do you wish to request the book?
Anti-tumor efficacy of a potent and selective non-covalent KRASG12D inhibitor
Please be aware that the book you have requested cannot be checked out. If you would like to checkout this book, you can reserve another copy
We have requested the book for you!
Your request is successful and it will be processed during the Library working hours. Please check the status of your request in My Requests.
Oops! Something went wrong.
Looks like we were not able to place your request. Kindly try again later.
Journal Article
Anti-tumor efficacy of a potent and selective non-covalent KRASG12D inhibitor
2022
Overview
Recent progress in targeting KRAS
G12C
has provided both insight and inspiration for targeting alternative KRAS mutants. In this study, we evaluated the mechanism of action and anti-tumor efficacy of MRTX1133, a potent, selective and non-covalent KRAS
G12D
inhibitor. MRTX1133 demonstrated a high-affinity interaction with GDP-loaded KRAS
G12D
with
K
D
and IC
50
values of ~0.2 pM and <2 nM, respectively, and ~700-fold selectivity for binding to KRAS
G12D
as compared to KRAS
WT
. MRTX1133 also demonstrated potent inhibition of activated KRAS
G12D
based on biochemical and co-crystal structural analyses. MRTX1133 inhibited ERK1/2 phosphorylation and cell viability in
KRAS
G12D
-mutant cell lines, with median IC
50
values of ~5 nM, and demonstrated >1,000-fold selectivity compared to
KRAS
WT
cell lines. MRTX1133 exhibited dose-dependent inhibition of KRAS-mediated signal transduction and marked tumor regression (≥30%) in a subset of
KRAS
G12D
-mutant cell-line-derived and patient-derived xenograft models, including eight of 11 (73%) pancreatic ductal adenocarcinoma (PDAC) models. Pharmacological and CRISPR-based screens demonstrated that co-targeting KRAS
G12D
with putative feedback or bypass pathways, including EGFR or PI3Kα, led to enhanced anti-tumor activity. Together, these data indicate the feasibility of selectively targeting KRAS mutants with non-covalent, high-affinity small molecules and illustrate the therapeutic susceptibility and broad dependence of
KRAS
G12D
mutation-positive tumors on mutant KRAS for tumor cell growth and survival.
A potent and selective inhibitor of KRAS
G12D
, the most common mutant form of the KRAS oncoprotein, has anti-tumor efficacy in multiple pre-clinical cancer models, opening the possibility to therapeutically target this highly prevalent oncogenic driver.
