Structure-Guided Design of Potent and Selective Pyrimidylpyrrole Inhibitors of Extracellular Signal-Regulated Kinase (ERK) Using Conformational Control

Aronov, Alex M.; Tang, Qing; Martínez-Botella, Gabriel; Bemis, Guy W.; Cao, Jingrong; Chen, Guanjing; Ewing, Nigel P.; Ford, Pamella J.; Germann, Ursula A.; Green, Jeremy; Hale, Michael R.; Jacobs, Marc; Janetka, James W.; Maltais, François; Markland, William; Namchuk, Mark; Nanthakumar, Suganthini; Poondru, Srinivasu; Straub, Judy; Haar, Ernst ter; Xie, Xin

doi:10.1021/jm900630q

Cited by 137 publications

(131 citation statements)

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“…Following extensive optimization of leads originally identified using a high-throughput, small-molecule screen (29), a novel adenosine triphosphate (ATP)-competitive ERK1/2 inhibitor, BVD-523 (ulixertinib) was identified (Fig. 1A).…”

Section: Resultsmentioning

confidence: 99%

Targeting the MAPK Signaling Pathway in Cancer: Promising Preclinical Activity with the Novel Selective ERK1/2 Inhibitor BVD-523 (Ulixertinib)

Germann

Furey

Markland

et al. 2017

Molecular Cancer Therapeutics

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190

145

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Aberrant activation of signaling through the RAS-RAF-MEK-ERK (MAPK) pathway is implicated in numerous cancers, making it an attractive therapeutic target. Although BRAF and MEK-targeted combination therapy has demonstrated significant benefit beyond single-agent options, the majority of patients develop resistance and disease progression after approximately 12 months. Reactivation of ERK signaling is a common driver of resistance in this setting. Here we report the discovery of BVD-523 (ulixertinib), a novel, reversible, ATP-competitive ERK1/2 inhibitor with high potency and ERK1/2 selectivity. In vitro BVD-523 treatment resulted in reduced proliferation and enhanced caspase activity in sensitive cells. Interestingly, BVD-523 inhibited phosphorylation of target substrates despite increased phosphorylation of ERK1/2. In in vivo xenograft studies, BVD-523 showed dose-dependent growth inhibition and tumor regression. BVD-523 yielded synergistic antiproliferative effects in a BRAF V600E -mutant melanoma cell line xenograft model when used in combination with BRAF inhibition. Antitumor activity was also demonstrated in in vitro and in vivo models of acquired resistance to singleagent and combination BRAF/MEK-targeted therapy. On the basis of these promising results, these studies demonstrate BVD-523 holds promise as a treatment for ERK-dependent cancers, including those whose tumors have acquired resistance to other treatments targeting upstream nodes of the MAPK pathway. Assessment of BVD-523 in clinical trials is underway

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Section: Resultsmentioning

confidence: 99%

Targeting the MAPK Signaling Pathway in Cancer: Promising Preclinical Activity with the Novel Selective ERK1/2 Inhibitor BVD-523 (Ulixertinib)

Germann

Furey

Markland

et al. 2017

Molecular Cancer Therapeutics

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190

145

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“…To further elucidate the mechanism of action of SCH772984, we compared its mitogen-activated protein kinase (MAPK) pathway inhibition with that of the previously described ATP-competitive ERK inhibitor VTX-11e ( 12,13 ). In the BRAF V600E -mutant A375 melanoma cell line, both compounds inhibited the formation of phospho-RSK in a dose-dependent manner ( Fig.…”

Section: Research Briefmentioning

confidence: 99%

Discovery of a Novel ERK Inhibitor with Activity in Models of Acquired Resistance to BRAF and MEK Inhibitors

et al. 2013

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The high frequency of activating RAS or BRAF mutations in cancer provides strong rationale for targeting the mitogen-activated protein kinase (MAPK) pathway. Selective BRAF and MAP-ERK kinase (MEK) inhibitors have shown clinical effi cacy in patients with melanoma. However, the majority of responses are transient, and resistance is often associated with pathway reactivation of the extracellular signal-regulated kinase (ERK) signaling pathway. Here, we describe the identifi cation and characterization of SCH772984, a novel and selective inhibitor of ERK1/2 that displays behaviors of both type I and type II kinase inhibitors. SCH772984 has nanomolar cellular potency in tumor cells with mutations in BRAF , NRAS , or KRAS and induces tumor regressions in xenograft models at tolerated doses. Importantly, SCH772984 effectively inhibited MAPK signaling and cell proliferation in BRAF or MEK inhibitor-resistant models as well as in tumor cells resistant to concurrent treatment with BRAF and MEK inhibitors. These data support the clinical development of ERK inhibitors for tumors refractory to MAPK inhibitors. SIGNIFICANCE: BRAF and MEK inhibitors have activity in MAPK-dependent cancers with BRAF or RAS mutations. However, resistance is associated with pathway alterations resulting in phospho-ERK reactivation. Here, we describe a novel ERK1/2 kinase inhibitor that has antitumor activity in MAPK inhibitor-naïve and MAPK inhibitor-resistant cells containing BRAF or RAS mutations. Cancer Discov; 3(7); 742-50.

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“…14) and G-573 (Genentech; ref. 15), as well as the ERK inhibitor (12,13), to evaluate the effects of MEK and ERK inhibition. Selectivity of the ERK inhibitor for ERK1/2 across a panel of kinases, and for KRAS mutant versus matched normal cells, is provided in Supplementary Fig.…”

Section: Compounds and Cell Viability Experimentsmentioning

confidence: 99%

“…Nevertheless, examples of selective ERK1/2 inhibitors have been reported and are currently in preclinical development (12,13). In this study, we set out to characterize the mechanisms of acquired resistance to MEK allosteric inhibitors in cancer cell lines harboring oncogenic K-ras mutations and identify strategies to overcome this resistance, with a focus on cotargeting ERK and MEK.…”

Section: Introductionmentioning

confidence: 99%

ERK Inhibition Overcomes Acquired Resistance to MEK Inhibitors

Hatzivassiliou¹,

Liu²,

O’Brien³

et al. 2012

Molecular Cancer Therapeutics

192

155

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The RAS/RAF/MEK pathway is activated in more than 30% of human cancers, most commonly via mutation in the K-ras oncogene and also via mutations in BRAF. Several allosteric mitogen-activated protein/ extracellular signal-regulated kinase (MEK) inhibitors, aimed at treating tumors with RAS/RAF pathway alterations, are in clinical development. However, acquired resistance to these inhibitors has been documented both in preclinical and clinical samples. To identify strategies to overcome this resistance, we have derived three independent MEK inhibitor-resistant cell lines. Resistance to allosteric MEK inhibitors in these cell lines was consistently linked to acquired mutations in the allosteric binding pocket of MEK. In one cell line, concurrent amplification of mutant K-ras was observed in conjunction with MEK allosteric pocket mutations. Clonal analysis showed that both resistance mechanisms occur in the same cell and contribute to enhanced resistance. Importantly, in all cases the MEK-resistant cell lines retained their addiction to the mitogenactivated protein kinase (MAPK) pathway, as evidenced by their sensitivity to a selective inhibitor of the ERK1/2 kinases. These data suggest that tumors with acquired MEK inhibitor resistance remain dependent on the MAPK pathway and are therefore sensitive to inhibitors that act downstream of the mutated MEK target. Importantly, we show that dual inhibition of MEK and ERK by small molecule inhibitors was synergistic and acted to both inhibit the emergence of resistance, as well as to overcome acquired resistance to MEK inhibitors. Therefore, our data provide a rationale for cotargeting multiple nodes within the MAPK signaling cascade in K-ras mutant tumors to maximize therapeutic benefit for patients.

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Structure-Guided Design of Potent and Selective Pyrimidylpyrrole Inhibitors of Extracellular Signal-Regulated Kinase (ERK) Using Conformational Control

Cited by 137 publications

References 9 publications

Targeting the MAPK Signaling Pathway in Cancer: Promising Preclinical Activity with the Novel Selective ERK1/2 Inhibitor BVD-523 (Ulixertinib)

Targeting the MAPK Signaling Pathway in Cancer: Promising Preclinical Activity with the Novel Selective ERK1/2 Inhibitor BVD-523 (Ulixertinib)

Discovery of a Novel ERK Inhibitor with Activity in Models of Acquired Resistance to BRAF and MEK Inhibitors

ERK Inhibition Overcomes Acquired Resistance to MEK Inhibitors

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