- |||||||||| ARS-1620 / Kura Oncology, J&J, Araxes Pharma
Journal, PD(L)-1 Biomarker, IO biomarker: KRas plays a negative role in regulating IDO1 expression. (Pubmed Central) - Nov 18, 2024
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.
- |||||||||| ARS-1620 / Kura Oncology, J&J, Araxes Pharma
Selective metalation of functionalized quinazolines to enable discovery and advancement of covalent KRAS inhibitors (Hybrid; Room 346 (Ernest N. Morial Convention Center)) - Mar 12, 2024 - Abstract #ACSSp2024ACS_Sp_10757;
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.
- |||||||||| Krazati (adagrasib) / Mirati, ARS-1620 / Kura Oncology, J&J, Araxes Pharma, Lumakras (sotorasib) / Amgen
Synergism of KRAS G12C Inhibitor and mTOR Inhibitor in Lung Adenocarcinoma and Squamous Cell Carcinoma (Exhibit Hall) - Jul 25, 2023 - Abstract #IASLCWCLC2023IASLC_WCLC_1213;
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.
- |||||||||| ARS-1620 / Kura Oncology, J&J, Araxes Pharma
Journal: AzidoTMT Enables Direct Enrichment and Highly Multiplexed Quantitation of Proteome-Wide Functional Residues. (Pubmed Central) - Jul 10, 2023
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.
- |||||||||| ARS-1620 / Kura Oncology, J&J, Araxes Pharma
Impact of KRAS oncogenic signaling in tumorigenesis and immune evasion driven by extracellular vesicles (EVs) (Section 5; Poster Board #13) - Mar 14, 2023 - Abstract #AACR2023AACR_6682;
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.
- |||||||||| ARS-1620 / Kura Oncology, J&J, Araxes Pharma, Tagrisso (osimertinib) / AstraZeneca
Journal: Multiscale Analysis and Validation of Effective Drug Combinations Targeting Driver KRAS Mutations in Non-Small Cell Lung Cancer. (Pubmed Central) - Jan 22, 2023
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.
- |||||||||| adagrasib (MRTX849) / Mirati, ARS-1620 / Kura Oncology, J&J, Araxes Pharma, Lumakras (sotorasib) / Amgen
Journal: Fluorescent Biosensor for Measuring Ras Activity in Living Cells. (Pubmed Central) - Sep 30, 2022
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.
- |||||||||| ARS-1620 / Kura Oncology, J&J, Araxes Pharma
Journal, IO biomarker: A covalent inhibitor of K-Ras(G12C) induces MHC class I presentation of haptenated peptide neoepitopes targetable by immunotherapy. (Pubmed Central) - Sep 20, 2022
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.
- |||||||||| ARS-1620 / Kura Oncology, J&J, Araxes Pharma
Journal: Discovery of novel Quinazoline-based KRAS G12C inhibitors as potential anticancer agents. (Pubmed Central) - Sep 10, 2022
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.
- |||||||||| ARS-1620 / Kura Oncology, J&J, Araxes Pharma
Journal, PD(L)-1 Biomarker, IO biomarker: Expression of IDO1 is regulated via Ras signaling pathways. (Pubmed Central) - May 14, 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 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.
- |||||||||| adagrasib (MRTX849) / Mirati, ARS-1620 / Kura Oncology, J&J, Araxes Pharma, Lumakras (sotorasib) / Amgen
Journal: Development of a biotin-streptavidin-enhanced enzyme-linked immunosorbent assay (BA-ELISA) for high-throughput screening of KRAS inhibitors. (Pubmed Central) - May 6, 2022
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.
- |||||||||| ARS-1620 / Kura Oncology, J&J
Journal: Cell-type Specific Adaptive Signaling Responses to KRASG12C inhibition. (Pubmed Central) - Mar 17, 2022
Our phosphoproteomic study identified cell-type adaptive responses to KRASG12C inhibitors. Markers and targets associated with ERBB2/3 signaling in epithelial subtype and FGFR1/AXL signaling in mesenchymal subtype should be considered in patient enrichment schemes with KRASG12C inhibitors.
- |||||||||| ARS-1620 / Kura Oncology, J&J, Araxes Pharma
Oncogenic KRas plays a significant role in regulating expression of IDO1 (E-Poster Website) - Mar 9, 2022 - Abstract #AACR2022AACR_7027;
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.
- |||||||||| ARS-1620 / Kura Oncology, J&J
Journal: Discovery of novel quinazoline-based covalent inhibitors of KRAS G12C with various cysteine-targeting warheads as potential anticancer agents. (Pubmed Central) - Oct 14, 2021
A series of novel quinazoline analogs with a variety of cysteine-targeting warheads (electrophiles) were designed and synthesized based on ARS-1620 as covalent KRAS G12C inhibitors...The high binding affinity of LLK10 was further confirmed by the isothermal titration calorimetry (ITC) assay in which LLK10 exhibited a K of 115 nM for binding to KRAS G12C. These results suggest that the novel covalent inhibitors of KRAS G12C with different warheads deserve further investigation as potential anticancer agents.
- |||||||||| KO-947 / Kura Oncology, Araxes Pharma
Enrollment change, Trial completion date, Trial termination, Trial primary completion date, Metastases: First-in-Human Study of KO-947 in Non-Hematological Malignancies (clinicaltrials.gov) - Jan 26, 2021
P1, N=62, Terminated,
N=100 --> 62 | Trial completion date: Dec 2020 --> Jun 2020 | Active, not recruiting --> Terminated | Trial primary completion date: Dec 2020 --> Jun 2020; Due to a strategic business decision Kura has stopped development of KO-947. Neither safety nor efficacy reasons were the cause of study termination.
- |||||||||| ARS-1620 / Kura Oncology, J&J, sotorasib (AMG 510) / Amgen
Journal: Vertical pathway inhibition overcomes adaptive feedback resistance to KRASG12C inhibition. (Pubmed Central) - Dec 18, 2020
Neither safety nor efficacy reasons were the cause of study termination. These data identify feedback reactivation of wild type RAS as a key mechanism of adaptive resistance to KRASinhibitors and highlight the potential importance of vertical inhibition strategies to enhance the clinical efficacy of KRASinhibitors.
- |||||||||| Keytruda (pembrolizumab) / Merck (MSD), Thalomid (thalidomide) / Fujimoto, BMS
[VIRTUAL] Emerging Mechanisms to Target KRAS Directly (Scientific Program Auditorium) - Dec 4, 2020 - Abstract #IASLCWCLC2020IASLC_WCLC_215;
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
- |||||||||| ARS-1620 / Kura Oncology, J&J
Journal, Combination therapy: Development of combination therapies to maximize the impact of KRAS-G12C inhibitors in lung cancer. (Pubmed Central) - Sep 1, 2020
Adding mTOR and IGF1R inhibitors to ARS-1620 greatly improves its effectiveness on KRAS-G12C mutant lung cancer cells in vitro and in mouse models. This provides a rationale for the design of combination treatments to enhance the impact of the KRAS-G12C inhibitors, which are now entering clinical trials.
- |||||||||| ARS-1620 / Kura Oncology, J&J
[VIRTUAL] Chemical strategies for drugging undruggable targets in oncology (On Demand Oral) - Aug 20, 2020 - Abstract #ACSFall2020ACS-Fall_6022;
I will discuss a new genome wide Crispr-i screen in K-RasG12C mutant cells treated with ARS-1620 to identify collateral dependencies which can be targeted in the clinic. I will also discuss ways to leverage immune cell killing of K-RasG12C cells treated with ARS-1620.
- |||||||||| ARS-1620 / Kura Oncology, J&J
[VIRTUAL] Chemical strategies for drugging undruggable targets in oncology (Broadcast) - Aug 20, 2020 - Abstract #ACSFall2020ACS-Fall_332;
I will discuss a new genome wide Crispr-i screen in K-RasG12C mutant cells treated with ARS-1620 to identify collateral dependencies which can be targeted in the clinic. I will also discuss ways to leverage immune cell killing of K-RasG12C cells treated with ARS-1620.
- |||||||||| ARS-1620 / Kura Oncology, J&J
Journal: An essential role for Argonaute 2 in EGFR-KRAS signaling in pancreatic cancer development. (Pubmed Central) - Aug 19, 2020
ARS-1620 (G12C-specific inhibitor) disrupts the KRAS-AGO2 interaction, suggesting that the interaction is targetable. Altogether, our study supports a biphasic model of pancreatic cancer development: an AGO2-independent early phase of PanIN formation reliant on EGFR-RAS signaling, and an AGO2-dependent phase wherein the mutant KRAS-AGO2 interaction is critical for PDAC progression.
- |||||||||| KO-947 / Kura Oncology, Araxes Pharma
Trial completion date, Trial primary completion date, Metastases: First-in-Human Study of KO-947 in Non-Hematological Malignancies (clinicaltrials.gov) - Jun 23, 2020
P1, N=100, Active, not recruiting,
Altogether, our study supports a biphasic model of pancreatic cancer development: an AGO2-independent early phase of PanIN formation reliant on EGFR-RAS signaling, and an AGO2-dependent phase wherein the mutant KRAS-AGO2 interaction is critical for PDAC progression. Trial completion date: Aug 2020 --> Dec 2020 | Trial primary completion date: Feb 2020 --> Dec 2020
- |||||||||| Adaptive resistance mechanisms to KRASG12C specific inhibitors (Virtual Meeting II: All Session Times Are U.S. EDT) - May 16, 2020 - Abstract #AACRII2020AACR-II_4628;
Lastly, our results suggest that cells sensitive to combination with either HER TKI or FGFR TKI with ARS-1620 are also demonstrating combination effects with SHP2 inhibition (SHP099)...Results suggest a more important role of pan-HER inhibition compared with EGFR inhibition. These data may guide biomarker development strategies, especially those that reflect adaptive signaling responses, to predict clinically effective combination strategies in diverse group of KRASG12C mutant lung cancer.
- |||||||||| ARS-1620 / Kura Oncology, J&J
AGO2 interaction limits wild type RAS activation yet essential for disease progression in oncogenic KRAS driven cancers (Virtual Meeting II: E-Posters) - May 16, 2020 - Abstract #AACRII2020AACR-II_17;
Further, using cell line models, we also showed that phosphorylation of AGO2Y393 by EGFR disrupted the interaction of RASWT with AGO2 at the membrane, but did not affect the interaction of mutant KRAS with AGO2. On the other hand, ARS-1620, a G12C-specific inhibitor, disrupted the KRASG12C-AGO2 interaction specifically in cells harboring this mutant, demonstrating that the oncogenic KRAS-AGO2 interaction can be pharmacologically targeted.Altogether, our findings reveal that the AGO2 interaction regulates RASWT and is essential for mutant KRAS driven oncogenesis.
- |||||||||| ARS-1620 / Kura Oncology, J&J
Journal, Combination therapy: KRAS G12C NSCLC models are sensitive to direct targeting of KRAS in combination with PI3K inhibition. (Pubmed Central) - Mar 2, 2020
On the other hand, ARS-1620, a G12C-specific inhibitor, disrupted the KRASG12C-AGO2 interaction specifically in cells harboring this mutant, demonstrating that the oncogenic KRAS-AGO2 interaction can be pharmacologically targeted.Altogether, our findings reveal that the AGO2 interaction regulates RASWT and is essential for mutant KRAS driven oncogenesis. Our findings suggest that signaling adaptation can in some instances limit the efficacy of ARS1620 but combination with PI3K inhibitors can overcome this resistance.
- |||||||||| KO-947 / Kura Oncology, Araxes Pharma
Enrollment closed, Enrollment change, Trial completion date, Trial primary completion date, Metastases: First-in-Human Study of KO-947 in Non-Hematological Malignancies (clinicaltrials.gov) - Mar 2, 2020
P1, N=100, Active, not recruiting,
Our findings suggest that signaling adaptation can in some instances limit the efficacy of ARS1620 but combination with PI3K inhibitors can overcome this resistance. Recruiting --> Active, not recruiting | N=72 --> 100 | Trial completion date: Apr 2020 --> Aug 2020 | Trial primary completion date: Oct 2019 --> Feb 2020
- |||||||||| Review, Journal: Targeting ERK1/2 protein-serine/threonine kinases in human cancers. (Pubmed Central) - Feb 16, 2020
The best treatments include the combination of B-Raf and MEK inhibitors (dabrafenib and trametinib, encorafenib and binimetinib, vemurafenib and cobimetanib)...Ulixertinib, MK-8353, and GDC-0994 are orally effective, potent, and specific inhibitors of ERK1/2 that are in early clinical trials for the treatment of various advanced/metastatic solid tumors...The decrease in RSK phosphorylation appears to be a result of ERK inhibition and the decrease in ERK1/2 phosphorylation is related to the inability of MEK to catalyze the phosphorylation of the ERK-MK-8353 complex; these decreases characterize the ERK dual mechanism inhibition paradigm. Additional work will be required to determine whether ERK inhibitors will be successful in the clinic and are able to forestall the development of drug resistance of the MAP kinase pathway.
- |||||||||| KO-947 / Kura Oncology, Araxes Pharma
Enrollment open, Metastases: First-in-Human Study of KO-947 in Non-Hematological Malignancies (clinicaltrials.gov) - Apr 14, 2017
P1, N=72, Recruiting,
Additional work will be required to determine whether ERK inhibitors will be successful in the clinic and are able to forestall the development of drug resistance of the MAP kinase pathway. Not yet recruiting --> Recruiting
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