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...
Autophagy-dependent longevity models in C. elegans display altered lipid storage profiles, but the contribution of lipid distribution to life-span extension is not fully understood. Here we report that lipoprotein production, autophagy and lysosomal lipolysis are linked to modulate life span in a conserved fashion. We find that overexpression of the yolk lipoprotein VIT/vitellogenin reduces the life span of long-lived animals by impairing the induction of autophagy-related and lysosomal genes necessary for longevity. Accordingly, reducing vitellogenesis increases life span via induction of autophagy and lysosomal lipolysis. Life-span extension due to reduced vitellogenesis or enhanced lysosomal lipolysis requires nuclear hormone receptors (NHRs) NHR-49 and NHR-80, highlighting novel roles for these NHRs in lysosomal lipid signaling. In dietary-restricted worms and mice, expression of VIT and hepatic APOB (apolipoprotein B), respectively, are significantly reduced, suggesting a conserved longevity mechanism. Altogether, our study demonstrates that lipoprotein biogenesis is an important mechanism that modulates aging by impairing autophagy and lysosomal lipolysis.
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.
KRAS is the most frequently mutated oncogene in cancer and drives uncontrolled growth through hyperactivation of the MAPK pathway. Significant progress has been made in the past several years to directly target KRASG12C with the FDA approval of sotorasib and the reported clinical activity of adagrasib (MRTX849). Despite these remarkable breakthroughs, additional therapies that enhance the depth and duration of response to KRASG12C inhibitors provide the opportunity to build upon the initial progress. SOS proteins are guanine nucleotide exchange factors (GEFs) that transduce receptor tyrosine kinase (RTK) signaling from the cell surface and facilitate the activation of RAS family proteins. In addition, SOS1 is a target of negative feedback signaling following RAS-mediated activation of the RAF-MEK-ERK cascade. Thus, SOS proteins represent a significant therapeutic node that maintains RAS pathway equilibrium as well as oncogenic signaling dynamics. Here we highlight the discovery and preclinical evaluation of MRTX0902, a potent, selective, and orally bioavailable inhibitor of SOS1 presently in IND-enabling studies. A structure-based approach was used to identify a novel chemical series that disrupts the protein-protein interaction between SOS1 and KRAS, thereby preventing SOS1-mediated GTP-exchange on GDP-bound KRAS. Considering MRTX849 preferentially binds to inactive GDP-bound KRASG12C, targeting SOS1 in this genetic context increases the ability of MRTX849 to bind and inhibit KRASG12C. The combination of MRTX0902 with MRTX849 enhances the depth and durability of an anti-tumor response when compared to MRTX849 alone in pre-clinical KRASG12C tumor models. MRTX0902 augments additional targeted therapies across a variety of RAS-addicted tumors, indicating that SOS1 inhibition is effective against a broad spectrum of mutations within the MAPK pathway. Furthermore, drug-anchored CRISPR experiments with MRTX0902 and MRTX849 uncovered a previously underappreciated functional role of the SOS1 paralog, SOS2, in KRAS-addicted tumors. In addition to aiding in the understanding of SOS and RAS family signaling dynamics, these studies implicate SOS2 as a potential cancer drug target in the context of SOS1/KRASG12C inhibition. In summary, we have used a structure-based approach to discover a SOS1 inhibitor that augments the anti-tumor activity of MRTX849 and additional targeted MAPK pathway inhibitors. We anticipate our findings to translate into the clinic and make an impact in patients with RAS-addicted tumors. Citation Format: John M. Ketcham, Shilpi Khare, Niranjan Sudhakar, David M. Briere, Larry Yan, Jade Laguer, Laura Vegar, Darin Vanderpool, Jill Hallin, Lauren Hargis, Vickie Bowcut, David Lawson, Robin J. Gunn, Anthony Ivetac, Nicole C. Thomas, Barbara Saechao, Natalie Nguyen, Jeffrey Clarine, Lisa Rahbaek, Christopher R. Smith, Aaron C. Burns, Matthew A. Marx, James G. Christensen, Peter Olson, Jacob R. Haling. MRTX0902: A SOS1 inhibitor for therapeutic intervention of KRAS-driven cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr ND02.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.