Discovery of a Potent and Selective Oral Inhibitor of ERK1/2 (AZD0364) That Is Efficacious in Both Monotherapy and Combination Therapy in Models of Nonsmall Cell Lung Cancer (NSCLC)

Ward, Richard A.; Anderton, Mark; Bethel, Paul A.; Breed, J.; Cook, Calum; Davies, Emma; Dobson, Andrew; Dong, Zhiqiang; Fairley, Gary; Farrington, Paul; Feron, Lyman; Flemington, Vikki; Gibbons, Francis D.; Graham, M. A.; Greenwood, Ryan; Hanson, Lyndsey; Hopcroft, Philip; Howells, Rachel; Hudson, Julian A.; James, Michael J.; Jones, Clifford D.; Jones, Christopher R.; Li, Yongchao; Lamont, Scott G.; Lewis, Richard J.; Lindsay, Nicola; McCabe, James F.; McGuire, Thomas M.; Rawlins, Philip; Roberts, Karen; Sandin, Linda C.; Simpson, Iain; Swallow, Steve; Jia, Tang; Tomkinson, Gary; Tonge, Michael; Wang, Zhenhua; Zhai, Beibei

doi:10.1021/acs.jmedchem.9b01295

Cited by 52 publications

(43 citation statements)

References 23 publications

(42 reference statements)

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“…5a ). In the organoid setting, induction of foetal marker expression was not affected by selective inhibitors of FAK (VS-4718) 40 , 41 or SRC (eCF506) 42 , but it was significantly suppressed by inhibitors of MEK (AZD6244) 43 , 44 , ERK 45 , and YAP (verteporfin) 20 (Fig. 4e ), with efficacy of MEK and ERK inhibitors demonstrated by suppression of the canonical MAPK target Dusp6 (Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

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Oncogenic BRAF, unrestrained by TGFβ-receptor signalling, drives right-sided colonic tumorigenesis

et al. 2021

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Right-sided (proximal) colorectal cancer (CRC) has a poor prognosis and a distinct mutational profile, characterized by oncogenic BRAF mutations and aberrations in mismatch repair and TGFβ signalling. Here, we describe a mouse model of right-sided colon cancer driven by oncogenic BRAF and loss of epithelial TGFβ-receptor signalling. The proximal colonic tumours that develop in this model exhibit a foetal-like progenitor phenotype (Ly6a/Sca1+) and, importantly, lack expression of Lgr5 and its associated intestinal stem cell signature. These features are recapitulated in human BRAF-mutant, right-sided CRCs and represent fundamental differences between left- and right-sided disease. Microbial-driven inflammation supports the initiation and progression of these tumours with foetal-like characteristics, consistent with their predilection for the microbe-rich right colon and their antibiotic sensitivity. While MAPK-pathway activating mutations drive this foetal-like signature via ERK-dependent activation of the transcriptional coactivator YAP, the same foetal-like transcriptional programs are also initiated by inflammation in a MAPK-independent manner. Importantly, in both contexts, epithelial TGFβ-receptor signalling is instrumental in suppressing the tumorigenic potential of these foetal-like progenitor cells.

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Section: Resultsmentioning

confidence: 99%

“…All drugs were made up in DMSO, at a final concentration of 0.1%, which served as a vehicle control. Final drug concentrations were: VS-4718 40 , 41 (FAKi) at 1 μM, eCF506 42 (SRCi) at 50 nM, AZD6244 43 , 44 (MEKi) at 100 nM, ERKi 45 at 100 nM, and verteporfin 20 (YAPi) at 3 μM.…”

Section: Methodsmentioning

confidence: 99%

Oncogenic BRAF, unrestrained by TGFβ-receptor signalling, drives right-sided colonic tumorigenesis

et al. 2021

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“…shERK1 knockdown had little or no effect in both cases, suggesting that this is an ERK2-specific event. Next, we repeated this experiment with two ERK2 kinase inhibitors, AZD0364 and SCH772984 (Pegram et al, 2019; Ward et al, 2019). Cell viability data showed that both AZD0364 and SCH772984 significantly reduced the viability of KRAS G12D mutant GSU cells, but their inhibitory effects were significantly reduced by TP53 gene knockout (Figure 4B).…”

Section: Resultsmentioning

confidence: 99%

“…Similar to trametinib treatment, both AZD0364 and SCH772984 stabilized p53 protein levels, increased Puma expression and promoted PARP cleavage (Figure 5c). Phosphorylation of the ERK effector p90RSK, which is akin to the inhibitory activity of ERK2 inhibitors 37 , declined after AZD0364 and SCH772984 treatment. p21 expression was also decreased after treatment with trametinib or ERK2 inhibitors.…”

Section: Erk2 Inhibition Which Mimics Trametinib Treatment Promotesmentioning

confidence: 99%

Targeting KRAS-mutant stomach/colorectal tumours by disrupting the ERK2-p53 complex

Wang¹,

Xie²,

et al. 2020

Preprint

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KRAS is widely mutated in human cancers, resulting in nearly unchecked tumour proliferation and metastasis. No therapies have been developed for targeting KRAS-mutant tumours. Herein, we observed that KRAS-mutant stomach/colorectal tumour cells were hypersensitive to the MEK1/2 kinase inhibitor trametinib, which elicits strong apoptotic responses. Genome-wide screening revealed that TP53 is critical for executing trametinib-induced apoptosis of KRAS-mutant tumours, as validated by TP53 knockout and rescue experiments. Mechanistically, p53 physically associates with phosphorylated ERK2 in the presence of mutant KRAS, which inactivates p53 by preventing the recruitment of p300/CBP. Trametinib disrupts the p53-ERK2 complex by inhibiting ERK2 phosphorylation, allowing the recruitment of p300/CBP to acetylate p53 protein; acetylated p53 activates PUMA transcription and thereby promotes the apoptosis of KRAS-mutant tumours. Our study unveils an important role of the ERK2-p53 axis and provides a potential therapeutic strategy for treating KRAS-mutant cancer via ERK2 inhibition.

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“…A novel molecule selectively targeting ERK, SCH772984, induced tumor regression in mouse xenograft models with KRAS or NRAS mutations [154]. AZD0364 exhibited dose-and time-dependent modulation of ERK1/2-dependent signaling to result in tumor regression in sensitive BRAFand KRAS-mutant xenografts [157,158]. Another similar small molecule, BVD523 (ulixertinib), exhibited antitumor activity for MEK-BRAF in concurrent or single targeting in resistant models in vitro or in vivo [156].…”

Section: Erk Inhibitionmentioning

confidence: 99%

Emerging strategies to target RAS signaling in human cancer therapy

et al. 2021

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RAS mutations (HRAS, NRAS, and KRAS) are among the most common oncogenes, and around 19% of patients with cancer harbor RAS mutations. Cells harboring RAS mutations tend to undergo malignant transformation and exhibit malignant phenotypes. The mutational status of RAS correlates with the clinicopathological features of patients, such as mucinous type and poor differentiation, as well as response to anti-EGFR therapies in certain types of human cancers. Although RAS protein had been considered as a potential target for tumors with RAS mutations, it was once referred to as a undruggable target due to the consecutive failure in the discovery of RAS protein inhibitors. However, recent studies on the structure, signaling, and function of RAS have shed light on the development of RAS-targeting drugs, especially with the approval of Lumakras (sotorasib, AMG510) in treatment of KRASG12C-mutant NSCLC patients. Therefore, here we fully review RAS mutations in human cancer and especially focus on emerging strategies that have been recently developed for RAS-targeting therapy.

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Discovery of a Potent and Selective Oral Inhibitor of ERK1/2 (AZD0364) That Is Efficacious in Both Monotherapy and Combination Therapy in Models of Nonsmall Cell Lung Cancer (NSCLC)

Cited by 52 publications

References 23 publications

Oncogenic BRAF, unrestrained by TGFβ-receptor signalling, drives right-sided colonic tumorigenesis

Oncogenic BRAF, unrestrained by TGFβ-receptor signalling, drives right-sided colonic tumorigenesis

Targeting KRAS-mutant stomach/colorectal tumours by disrupting the ERK2-p53 complex

Emerging strategies to target RAS signaling in human cancer therapy

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