KRASG12D, the most common oncogenic KRAS mutation, is
a promising target for the treatment of solid tumors. However, when
compared to KRASG12C, selective inhibition of KRASG12D presents a significant challenge due to the requirement
of inhibitors to bind KRASG12D with high enough affinity
to obviate the need for covalent interactions with the mutant KRAS
protein. Here, we report the discovery and characterization of the
first noncovalent, potent, and selective KRASG12D inhibitor,
MRTX1133, which was discovered through an extensive structure-based
activity improvement and shown to be efficacious in a KRASG12D mutant xenograft mouse tumor model.
The ability to effectively target mutated KRAS has remained elusive despite decades of research. The recent identification of KRAS G12C inhibitors has provided an effective treatment option for patients harboring this particular mutation and has also provided insight toward targeting other KRAS mutants, including KRAS G12D . MRTX1133 was identified via a structure-based drug design (SBDD) strategy as a potent, selective, and non-covalent KRAS G12D inhibitor directed at the switch II binding pocket. MRTX1133 demonstrated a high-affinity interaction with KRAS G12D with KD or IC50 values each determined at ~0.2 pM or <2 nM using SPR direct binding or HTRF competition assays, respectively. MRTX1133 also demonstrated ~700-fold selectivity for KRAS G12D vs KRAS WT binding utilizing SPR. Interestingly, MRTX1133 demonstrated potent inhibition of active KRAS G12D using an HTRF effector interaction assay with a IC50 value of 9 nM. Insight toward the structural basis of binding of MRTX1133 to both the inactive GDP-bound and active GMPPCP-bound conformations of KRAS G12D is also provided by co-crystal structures. MRTX1133 demonstrated potent inhibition of ERK1/2 phosphorylation and cell viability in KRAS G12D -mutant cell lines with median IC50 values of ~5 nM. Consistent with binding affinity determination in cell-free systems, MRTX1133 demonstrated >1000-fold selectivity for inhibition of ERK1/2 phosphorylation in KRAS G12Dmutant cell lines compared with KRAS WT cell lines. Dose-dependent inhibition of KRASmediated signal transduction was also observed in multiple KRAS G12D -mutant tumor models in vivo. MRTX1133 demonstrated marked tumor regression (>30%) in a subset of KRAS G12Dmutant cell line-and patient-derived xenograft (PDX) models, including 8 out of 11 (73%) pancreatic ductal adenocarcinoma (PDAC) models evaluated. Pharmacological studies and CRISPR-based screens demonstrated co-targeting KRAS G12D in concert with putative feedback or bypass pathways including EGFR and PI3Kα led to enhanced anti-tumor activity relative to targeting each individual protein. Together, these data indicate the feasibility of utilizing SBDD approaches to selectively target alternative KRAS mutant variants with non-covalent, highaffinity small molecules targeting either the active or inactive state of KRAS. In addition, these data illustrate the therapeutic susceptibility and broad dependence of KRAS G12D mutationpositive tumors, including PDAC, on KRAS for tumor cell growth and survival.
SignificanceThe development of clinically active KRAS G12C -selective inhibitors represents a milestone achievement for the treatment of cancer; however, the discovery of additional KRAS-mutant selective inhibitors has remained elusive. MRTX1133 is a potent KRAS G12D -selective small molecule inhibitor, is active in vitro and in vivo, induces regression in multiple xenograft tumor models and demonstrates increased anti-tumor activity in rationally designed combinations. These data confirm KRAS G12D functions as an oncogenic driver, including in pancreat...
A new reagent for the enantioselective allylation of aliphatic aldehydes has been developed. The reagent is easily prepared in a single step from commercially available materials and may be stored without significant decomposition. The reactivity of the reagent is attributed to strain-release Lewis acidity.
The PRMT5•MTA
complex has recently emerged as a new synthetically
lethal drug target for the treatment of MTAP-deleted
cancers. Here, we report the discovery of development candidate MRTX1719. MRTX1719 is a potent and selective
binder to the PRMT5•MTA complex and selectively inhibits PRMT5
activity in MTAP-deleted cells compared to MTAP-wild-type cells. Daily oral administration of MRTX1719 to tumor xenograft-bearing mice demonstrated dose-dependent
inhibition of PRMT5-dependent symmetric dimethylarginine protein modification
in MTAP-deleted tumors that correlated with antitumor
activity. A 4-(aminomethyl)phthalazin-1(2H)-one hit
was identified through a fragment-based screen, followed by X-ray
crystallography, to confirm binding to the PRMT5•MTA complex.
Fragment growth supported by structural insights from X-ray crystallography
coupled with optimization of pharmacokinetic properties aided the
discovery of development candidate MRTX1719.
SOS1 is one of the major guanine nucleotide exchange
factors that
regulates the ability of KRAS to cycle through its “on”
and “off” states. Disrupting the SOS1:KRAS
G12C
protein–protein interaction (PPI) can increase the proportion
of GDP-loaded KRAS
G12C
, providing a strong mechanistic
rationale for combining inhibitors of the SOS1:KRAS complex with inhibitors
like MRTX849 that target GDP-loaded KRAS
G12C
. In this report,
we detail the design and discovery of MRTX0902—a potent, selective,
brain-penetrant, and orally bioavailable SOS1 binder that disrupts
the SOS1:KRAS
G12C
PPI. Oral administration of MRTX0902
in combination with MRTX849 results in a significant increase in antitumor
activity relative to that of either single agent, including tumor
regressions in a subset of animals in the MIA PaCa-2 tumor mouse xenograft
model.
It was found that solvent hydrogen bond basicity (SHBB) significantly affects the regiochemistry of the S(N)Ar reaction between secondary amines and activated polyfluoroarenes. A plausible mechanism involving a six-membered transition state is invoked for the formation of an ortho-substituted isomer, which is likely organized by a hydrogen bond. Evidence for this hypothesis is presented, and a regioselective amination reaction of activated polyfluoroarenes has been developed.
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