Discovery of hydroxyaniline amides as selective Extracellular Regulated Kinase (Erk) inhibitors

Zhu, Haiyuan; Desai, Jagdish; Deng, Yongqi; Cooper, Alan; Wang, James; Shipps, Jerry; Samatar, Ahmed A.; Carr, Donna; Windsor, William

doi:10.1016/j.bmcl.2015.01.049

Cited by 12 publications

(9 citation statements)

References 9 publications

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“…(and attendant conformational changes) and its ability to phosphorylate a substrate; it can therefore capture the inhibition of both inactive and activated ERK2 (Deng et al, 2014;Zhu et al, 2015).…”

Section: Fr180204mentioning

confidence: 99%

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ERK1/2 inhibitors: New weapons to inhibit the RAS-regulated RAF-MEK1/2-ERK1/2 pathway

Kidger

Sipthorp

Cook

2018

Pharmacology & Therapeutics

132

123

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The RAS-regulated RAF-MEK1/2-ERK1/2 signalling pathway is de-regulated in a variety of cancers due to mutations in receptor tyrosine kinases (RTKs), negative regulators of RAS (such as NF1) and core pathway components themselves (RAS, BRAF, CRAF, MEK1 or MEK2). This has driven the development of a variety of pharmaceutical agents to inhibit RAF-MEK1/2-ERK1/2 signalling in cancer and both RAF and MEK inhibitors are now approved and used in the clinic. There is now much interest in targeting at the level of ERK1/2 for a variety of reasons. First, since the pathway is linear from RAF-to-MEK-to-ERK then ERK1/2 are validated as targets per se. Second, innate resistance to RAF or MEK inhibitors involves relief of negative feedback and pathway re-activation with all signalling going through ERK1/2, validating the use of ERK inhibitors with RAF or MEK inhibitors as an up-front combination. Third, long-term acquired resistance to RAF or MEK inhibitors involves a variety of mechanisms (KRAS or BRAF amplification, MEK mutation, etc.) which re-instate ERK activity, validating the use of ERK inhibitors to forestall acquired resistance to RAF or MEK inhibitors. The first potent highly selective ERK1/2 inhibitors have now been developed and are entering clinical trials. They have one of three discrete mechanisms of action - catalytic, "dual mechanism" or covalent - which could have profound consequences for how cells respond and adapt. In this review we describe the validation of ERK1/2 as anti-cancer drug targets, consider the mechanism of action of new ERK1/2 inhibitors and how this may impact on their efficacy, anticipate factors that will determine how tumour cells respond and adapt to ERK1/2 inhibitors and consider ERK1/2 inhibitor drug combinations.

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Section: Fr180204mentioning

confidence: 99%

“…Current Biology, 9(7), 369-376. https://doi.org/10.1016/S0960- (Hancock et al, 2005) Development of compound 76: (Boston et al, 2011;Jung et al, 2013;Li et al, 2009) Compound (Deng et al, 2014;Lim et al, 2016;Morris et al, 2013;Zhu et al, 2015) ClinicalTrials. Phase I (Germann et al, 2015;Li et al, 2017) ClinicalTrials.…”

Section: (6)mentioning

confidence: 99%

ERK1/2 inhibitors: New weapons to inhibit the RAS-regulated RAF-MEK1/2-ERK1/2 pathway

Kidger

Sipthorp

Cook

2018

Pharmacology & Therapeutics

132

123

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“…These compounds include ulixertinib (BVD-523, an analog of the earlier generation compound VTX-11e) and ravoxertinib (GDC-0994) currently in early clinical trials [13, 38] as well as other preclinical compounds [39–44]. Another ATP-competitive inhibitor, SCH772984, was discovered through elaboration of a hit compound identified to bind to the unphosphorylated inactive form of ERK2 using a novel mass spectrometry-based approach [12, 45–47]. SCH772984 is a type II inhibitor with a “dual mechanism” of inhibition by virtue of its ability to downregulate ERK1/2 phosphorylation in cells as well as block substrate phosphorylation [48].…”

Section: Discussionmentioning

confidence: 99%

A high throughput assay to identify substrate-selective inhibitors of the ERK protein kinases

Miller

Muftuoglu

Turk

2017

Biochemical Pharmacology

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Extracellular signal-regulated kinases 1 and 2 (ERK1/2) phosphorylate a variety of substrates important for survival and proliferation, and their activity is frequently deregulated in tumors. ERK pathway inhibitors have shown clinical efficacy as anti-cancer drugs, but most patients eventually relapse due to reactivation of the pathway. One factor limiting the efficacy of current therapeutics is the difficulty in reaching clinically effective inhibition of the ERK pathway in the absence of on-target toxicities. Here, we describe an assay suitable for high throughput screening to discover substrate selective ERK1/2 inhibitors, which may have a larger therapeutic window than conventional inhibitors. Specifically, we aim to target a substrate-binding pocket within the ERK1/2 catalytic domain outside of the catalytic cleft. The assay uses an AlphaScreen format to detect phosphorylation of a high-efficiency substrate harboring an essential docking site motif. Pilot screening established that the assay is suitably robust for high-throughput screening. Importantly, the assay can be conducted at high ATP concentrations, which we show reduces the discovery of conventional ATP-competitive inhibitors. These studies provide the basis for high-throughput screens to discover new classes of non-conventional ERK1/2 inhibitors.

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“…The Automated Ligand Identification System (ALIS) (Annis et al, 2004) and Speedscreen system (Muckenschnabel et al, 2004) are two famous platforms of the “indirect” BA‐MS technique based on SEC. The two platforms have been applied to efficiently screen a variety of classes of protein targets including polymerases, kinases (Zhu et al, 2015; Hurzy et al, 2017), integral membrane proteins, G protein‐coupled receptors (GPCRs), and enzymes (Nakao et al, 2014). Several key examples of SEC based indirect BA‐MS are summarized in Table 3.…”

Section: Indirect Ba‐ms Methods Relying On Size Exclusion Chromatographymentioning

confidence: 99%

Label‐free Bio‐affinity Mass Spectrometry for Screening and Locating Bioactive Molecules

Tao

Yan

Cai

2019

Mass Spectrometry Reviews

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Despite the recent increase in the development of bioactive molecules in the drug industry, the enormous chemical space and lack of productivity are still important issues. Additional alternative approaches to screen and locate bioactive molecules are urgently needed. Label‐free bio‐affinity mass spectrometry (BA‐MS) provides opportunities for the discovery and development of innovative drugs. This review provides a comprehensive portrayal of BA‐MS techniques and of their applications in screening and locating bioactive molecules. After introducing the basic principles, alongside some application notes, the current state‐of‐the‐art of BA‐MS‐assisted drug discovery is discussed, including native MS, size‐exclusion chromatography‐MS, ultrafiltration‐MS, solid‐phase micro‐extraction‐MS, and cell membrane chromatography‐MS. Finally, several challenges and limitations of the current methods are summarized, with a view to potential future directions for BA‐MS‐assisted drug discovery. © 2019 John Wiley & Sons Ltd. Mass Spec Rev

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Discovery of hydroxyaniline amides as selective Extracellular Regulated Kinase (Erk) inhibitors

Cited by 12 publications

References 9 publications

ERK1/2 inhibitors: New weapons to inhibit the RAS-regulated RAF-MEK1/2-ERK1/2 pathway

ERK1/2 inhibitors: New weapons to inhibit the RAS-regulated RAF-MEK1/2-ERK1/2 pathway

A high throughput assay to identify substrate-selective inhibitors of the ERK protein kinases

Label‐free Bio‐affinity Mass Spectrometry for Screening and Locating Bioactive Molecules

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