ARS-1620 / Kura Oncology, J&J, Araxes Pharma - LARVOL DELTA

Dual inhibition of GTP-bound KRAS and mTOR in lung adenocarcinoma and squamous cell carcinoma harboring KRAS G12C. (PubMed, Cell Commun Signal) - "KRAS G12C inhibitor plus RAD001 consistently revealed synergism. Targeting KRAS G12C and mTOR abrogates the RAS-MEK-ERK and PI3K-AKT-mTOR pathways. Our data suggests that a combined strategy targeting GTP-bound KRAS G12C and mTOR shows promise for primary lung cancers with KRAS G12C mutations. This approach may also be effective even for lung cancers harboring KRAS G12C mutation but having different profiles."

Journal • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Sarcoma • Solid Tumor • Squamous Cell Carcinoma • KRAS

KRas plays a negative role in regulating IDO1 expression. (PubMed, Transl Oncol) - "Treatment with the KRasG12C-specific inhibitor, ARS-1620, significantly increased IDO1 expression, which inversely correlated with PD-L1 expression in the KRasG12C-mutant H358 cell line...Moreover, the induction of IDO1 expression following KRas inhibition appears to operate independently of the MAPK pathway. Our results propose that concurrent targeting of KRas and IDO1 could potentiate therapeutic efficacy in KRas-mutant cancers, overcoming resistance to immune checkpoint blockade."

IO biomarker • Journal • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • IDO1 • IFNG • KRAS • PD-1 • PD-L1

Contribution of Noncovalent Recognition and Reactivity to the Optimization of Covalent Inhibitors: A Case Study on KRasG12C. (PubMed, ACS Chem Biol) - "Our results revealed that the atropisomeric core of ARS-1620 is not indispensable for KRASG12C inhibition, the basic side chain has little effect on either binding step, and warheads affect the covalent reactivity but not the noncovalent binding. This type of analysis helps identify structural determinants of efficient covalent inhibition and may find use in the design of covalent agents."

Journal • Oncology • KRAS

Discovery of novel coumarin-based KRAS-G12C inhibitors from virtual screening and Rational structural optimization. (PubMed, Bioorg Chem) - "Especially, K45 exhibited strong antiproliferative potency on NCI-H23 and NCI-H358 cancer cells harboring KRAS-G12C with the IC50 values of 0.77 μM and 1.50 μM, which was 15 and 11 times as potent as positive drug ARS1620, respectively...Docking studies displayed that the 3-naphthylmethoxy moiety of K45 extended into the cryptic pocket formed by the residues Gln99 and Val9, which enhanced the interaction with the KRAS-G12C protein. These results indicated that K45 was a potent KRAS-G12C inhibitor worthy of further study."

Journal • Oncology • KRAS

Scaleup efforts on the production of the first-generation, atropisomeric covalent KRAS G12c inhibitors ARS-1620 and ARS-2102 (ACS-Sp 2024) - "A global deprotection followed by chemoselective functionalization afforded ARS-2102 in excellent yield and diastereomeric enrichment. This chromatography-free sequence was successfully executed on kilogram scale."

Oncology • KRAS

Selective metalation of functionalized quinazolines to enable discovery and advancement of covalent KRAS inhibitors (ACS-Sp 2024) - "Route scouting in support of multi-gram ARS-1620 batches led to a new synthetic approach that relies on metalation of substituted quinazolines at C7. The exquisite selectivity seen in this metalation formed the basis for a scalable route to kg quantities of compounds in this family and accelerated Medicinal Chemistry efforts as related intermediates became readily available."

Oncology • KRAS

Accelerating multiplexed profiling of protein-ligand interactions: High-throughput plate-based reactive cysteine profiling with minimal input. (PubMed, Cell Chem Biol) - "We further applied the platform to characterize new cellular targets of established drugs, uncovering that ARS-1620, a KRAS inhibitor, binds to and inhibits an off-target adenosine kinase ADK. The platform represents a major step forward to high-throughput proteome-wide evaluation of reactive cysteines."

Journal • KRAS

Identifying genes associated with resistance to KRAS G12C inhibitors via machine learning methods. (PubMed, Biochim Biophys Acta Gen Subj) - "Above genes were relevant to tumor cell resistance to targeted therapy. This study provides important insights into the molecular mechanisms underlying tumor cell resistance to KRAS inhibitor treatment."

Journal • Machine learning • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • BIRC5 • CKS1B • KRAS • RRM2 • TUBA1B

Synergism of KRAS G12C Inhibitor and mTOR Inhibitor in Lung Adenocarcinoma and Squamous Cell Carcinoma (IASLC-WCLC 2023) - "The frequency of KRAS G12C mutation is similar in adenocarcinoma and squamous cell carcinoma of lung. Combination of KRAS G12C inhibitor (AMG-510, MRTX849, and ARS-1620) and mTOR inhibitor (Everolimus) showed synergism in both adenocarcinoma and squamous cell carcinoma cell lines. The targetable somatic variant G12C in KARS should be explored in squamous cell carcinoma as well as in adenocarcinoma."

Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • KRAS

AzidoTMT Enables Direct Enrichment and Highly Multiplexed Quantitation of Proteome-Wide Functional Residues. (PubMed, J Proteome Res) - "We demonstrate its application in identifying cysteine on- and off-targets using a KRAS G12C covalent inhibitor ARS-1620...Lastly, we screened 20 sulfonyl fluoride-based compounds to demonstrate that the AT-MAPP assay is flexible for noncysteine functional residues such as tyrosine and lysine. Overall, we envision that 11plex-AzidoTMT will be a useful addition to the current toolbox for activity-based protein profiling and covalent drug development."

Journal • KRAS

Impact of KRAS oncogenic signaling in tumorigenesis and immune evasion driven by extracellular vesicles (EVs) (AACR 2023) - "We performed a comprehensive proteomic comparison between EVs isolated from H358 treated with ARS-1620 and those isolated from cells treated with DMSO (vehicle) and identified proteins involved in migration and invasion, such as LAMB-3, to be downregulated in EVs isolated from ARS-1620 treated cells. Ongoing studies aim to pinpoint the detailed mechanisms by which cancer cells utilize mutant KRAS signaling to promote loading of oncogenic cargo into EVs, and the resulting contributions to tumorigenesis and immune evasion."

Lung Cancer • Oncology • Sarcoma • Solid Tumor • KRAS

Multiscale Analysis and Validation of Effective Drug Combinations Targeting Driver KRAS Mutations in Non-Small Cell Lung Cancer. (PubMed, Int J Mol Sci) - "Gene expression studies revealed that MAPK expression is strongly correlated with decreased cellular proliferation following treatment with KRAS inhibitor BAY-293, but not treatment with ARS-1620 or osimertinib. These results indicate that our precision medicine pipeline may be used to identify compounds capable of synergizing with inhibitors of KRAS G12C, and to assess their likelihood of becoming drugs by understanding their behavior at the proteomic/interactomic scales."

Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS

Fluorescent Biosensor for Measuring Ras Activity in Living Cells. (PubMed, J Am Chem Soc) - "Furthermore, we showed that RasAR enables capture of KRasG12C inhibition dynamics in living cells upon treatment with KRasG12C covalent inhibitors, including ARS1620, Sotorasib, and Adagrasib. We found in living cells a residual Ras activity lingers for hours in the presence of these inhibitors. Together, RasAR represents a powerful molecular tool to enable live-cell interrogation of Ras activity and facilitate the development of Ras inhibitors."

Journal • Immunology • Oncology • HRAS • KRAS

A covalent inhibitor of K-Ras(G12C) induces MHC class I presentation of haptenated peptide neoepitopes targetable by immunotherapy. (PubMed, Cancer Cell) - "Using ARS1620-specific antibodies identified by phage display, we show that these haptenated MHC-I complexes can serve as tumor-specific neoantigens and that a bispecific T cell engager construct based on a hapten-specific antibody elicits a cytotoxic T cell response against KRAS G12C cells, including those resistant to direct KRAS G12C inhibition. With multiple K-RAS G12C inhibitors in clinical use or undergoing clinical trials, our results present a strategy to enhance their efficacy and overcome the rapidly arising tumor resistance."

IO biomarker • Journal • Oncology • KRAS

Discovery of novel Quinazoline-based KRAS G12C inhibitors as potential anticancer agents. (PubMed, Bioorg Med Chem) - "A series of novel quinazoline analogs were designed and synthesized based on ARS-1620 and LLK-10 (a KRAS inhibitor reported by us recently) as KRAS G12C inhibitors with a 5-nitrofuran-2-carboxylic acid warhead...Lastly, KS-19 possessed a benign toxicity profile without causing bone marrow suppression and any obvious morphological abnormalities in major organs of mice. Collectively, these results suggest that KS-19 represents a novel inhibitor of KRAS G12C worthy of further investigation as a potential anticancer agent."

Journal • Colon Cancer • Oncology • Solid Tumor • KRAS

Expression of IDO1 is regulated via Ras signaling pathways. (PubMed, FASEB J) - "In H358 lung carcinoma cells, IDO1 expression induced by IFN-γ was at least in part dependent on ERK activation, and treatment with ARS-1620, a covalent KRas inhibitor, suppressed IDO1 expression induced by IFN-γαμμα in a concentration-dependent manner...In addition, KRas downregulation by specific siRNAs decreased IFN-γ-induced IDO1 expression in A549 lung cancer cells. Taken together, our study strongly suggests that Ras/ERK signaling pathway plays an important role in promoting IDO1 expression induced by IFN-γ."

IO biomarker • Journal • Colon Cancer • Colorectal Cancer • Immunology • Inflammation • Lung Cancer • Oncology • Solid Tumor • IDO1 • IFNG • IL6 • KRAS • PD-L1

Oncogenic KRas plays a significant role in regulating expression of IDO1 (AACR 2022) - "In H358 lung carcinoma cells, IDO1 expression induced by IFN-γ was at least in part dependent on ERK activation, and treatment with ARS-1620, a covalent KRasG12C inhibitor, suppressed IDO1 expression induced by IFN-γ in a concentration-dependent manner...In addition, KRas downregulation by specific siRNAs decreased IFN-γ-induced IDO1 expression in A549 lung cancer cells. Taken together, our study strongly suggests that Ras/ERK signaling pathway plays an important role in promoting IDO1 expression induced by IFN-γ."

IO biomarker • Late-breaking abstract • Colon Cancer • Colorectal Cancer • Lung Cancer • Oncology • Solid Tumor • IDO1 • IFNG • IL6 • KRAS • PD-L1

Application of NanoBRET target engagement cellular assay for measurement of inhibitor binding to wild type and mutant RAS in live cells (AACR 2022) - "In addition, we are able to confirm the signaling inhibition of downstream phospho-ERK1/2 by KRAS (G12C)-specific inhibitors AMG 510 (Sotorasib), ARS-1620, MRTX849, and MRTX1257 in MIA PaCa-2 pancreas and SW837 colon cancer cells bearing KRAS (G12C) mutation by Western blot assay. Our results suggest NanoBRETTM TE cellular assay can serve as a great tool to facilitate RAS pathway drug discovery against human cancers."

Colon Cancer • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Solid Tumor • HRAS • KRAS

Overexpression of ABCB1 Associated With the Resistance to the KRAS-G12C Specific Inhibitor ARS-1620 in Cancer Cells. (PubMed, Front Pharmacol) - "In mechanism-based studies, [H] -paclitaxel accumulation assay revealed that ARS-1620 could be competitively pumped out by ABCB1. ARS-1620 acquired a high docking score in computer molecular docking analysis, implying ARS-1620 could intensely interact with ABCB1 transporters. Taken all together, these data indicated that ARS-1620 is a substrate for ABCB1, and the potential influence of ARS-1620-related cancer therapy on ABCB1-overexpressing cancer cells should be considered in future clinical applications."

Journal • Oncology • ABCB1 • KRAS

Discovery of ARS-1620 analogs as KRas G12C inhibitors with high in vivo antitumor activity. (PubMed, Bioorg Chem) - "Lastly, K20 exhibited benign toxicity profiles without causing bone marrow suppression and any other apparent toxicity to major organs of mice. Collectively, these results indicate that K20 is a KRas G12C inhibitor deserving further investigation."

Journal • Preclinical • Oncology • Solid Tumor • KRAS

Classical RAS proteins are not essential for paradoxical ERK activation induced by RAF inhibitors. (PubMed, Proc Natl Acad Sci U S A) - "In this study, we showed that LY3009120, a pan-RAF inhibitor, can unexpectedly cause paradoxical ERK activation in KRAS-dependent lung cancer cell lines, when KRAS is inhibited by ARS1620, a KRAS inhibitor. We further showed that the MRAS/SHOC2 complex is required for this process. This study highlights the complexity of the allosteric RAF regulation by RAF inhibitors, and the importance of other RAS-related proteins in this process."

Journal • Lung Cancer • Oncology • Solid Tumor • KRAS

Development of a biotin-streptavidin-enhanced enzyme-linked immunosorbent assay (BA-ELISA) for high-throughput screening of KRAS inhibitors. (PubMed, SLAS Discov) - "Furthermore, BA-ELISA can also be expanded to determine the cellular potency of the inhibitors using KRAS mutant living cells. Using three previously disclosed compounds, ARS-1620, AMG 510, and MRTX849, we demonstrated that BA-ELISA is a highly sensitive, specific, and robust method for high-throughput screening of KRAS inhibitors."

Journal • Oncology • KRAS

RAS-Driven Macropinocytosis of Albumin or Dextran Reveals Mutation-Specific Target Engagement of RAS p.G12C Inhibitor ARS-1620 by NIR-Fluorescence Imaging. (PubMed, Mol Imaging Biol) - "These data provide a novel approach using NIR-labeled human serum albumin to identify and monitor RAS-driven tumors as well as evaluate the on-target efficacy in vivo of inhibitors, such as ARS-1620."

Journal • Gastrointestinal Cancer • Hepatology • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Solid Tumor • KRAS

[VIRTUAL] Emerging Mechanisms to Target KRAS Directly (IASLC-WCLC 2020) - P1, P1/2 | "In preclinical studies, CD8 T cell responses to KRAS antigens were greatly enhanced following vaccination with mRNA encoding KRAS mutations.[1] A phase I study utilizing V941 with or without pembrolizumab in patients with KRAS mutant advanced or metastatic NSCLC, colorectal cancer (CRC) or pancreatic adenocarcinoma is currently recruiting (NCT03948763, Table1)...The degrader library design was based on using a parental compound chemically related to the mutant-selective covalent inhibitor ARS-1620 as the KRASG12C warhead and thalidomide as the cereblon (CRBN) warhead...Table 1. Vaccine and T cell trials focused on KRAS"

IO biomarker • Colorectal Cancer • Gastrointestinal Cancer • Hepatology • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Solid Tumor • Targeted Protein Degradation • CD8 • CRBN • KRAS

Development and Preclinical Evaluation of Radiolabeled Covalent G12C-Specific Inhibitors for Direct Imaging of the Oncogenic KRAS Mutant. (PubMed, Mol Pharm) - "In vitro and in vivo studies have demonstrated the affinity, specificity, and capacity of [I]I-ARS-1620 for direct imaging of the oncogenic KRAS G12C mutant. This initial attempt allows us to directly screen the KRAS G12C mutant for the first time in vivo."

Journal • Preclinical • Oncology • KRAS