Discovery of (S)-1-(1-(4-Chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one (GDC-0994), an Extracellular Signal-Regulated Kinase 1/2 (ERK1/2) Inhibitor in Early Clinical Development

Blake, James F.; Burkard, Michael; Chan, Jocelyn; Chen, Huifen; Chou, Kang-Jye; Diaz, Dolores; Dudley, Danette A.; Gaudino, John J.; Gould, Stephen E.; Grina, Jonas; Hunsaker, Thomas; Liu, Lichuan; Martinson, Matthew; Moreno, David; Müeller, Lars; Orr, Christine; Pacheco, Patrícia; Qin, Ann; Rasor, Kevin; Ren, Li; Robarge, Kirk; Shahidi-Latham, Sheerin; Stults, Jeffrey; Sullivan, Francis X.; Wang, Weiru; Yin, Jianping; Zhou, Aihe; Belvin, Marcia; Merchant, Mark; Moffat, John G.; Schwarz, Jacob B.

doi:10.1021/acs.jmedchem.6b00389

Cited by 135 publications

(138 citation statements)

References 23 publications

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“…S5; refs. 40,41). Of note, both the control and resistant NOMO-1 lines displayed exquisite single agent sensitivity to the MEK1/2 inhibitor trametinib with 3-day IC 50 values less than 1 nmol/L (40).…”

Section: Hypothesis Generation and Testing Of Nomo-1 Mechanism Of Resmentioning

confidence: 99%

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Mechanisms of Pinometostat (EPZ-5676) Treatment–Emergent Resistance in MLL-Rearranged Leukemia

Campbell

Haladyna

Drubin

et al. 2017

Molecular Cancer Therapeutics

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DOT1L is a protein methyltransferase involved in the development and maintenance of MLL-rearranged (MLL-r) leukemia through its ectopic methylation of histones associated with wellcharacterized leukemic genes. Pinometostat (EPZ-5676), a selective inhibitor of DOT1L, is in clinical development in relapsed/ refractory acute leukemia patients harboring rearrangements of the MLL gene. The observation of responses and subsequent relapses in the adult trial treating MLL-r patients motivated preclinical investigations into potential mechanisms of pinometostat treatment-emergent resistance (TER) in cell lines confirmed to have MLL-r. TER was achieved in five MLL-r cell lines, KOPN-8, MOLM-13, MV4-11, NOMO-1, and SEM. Two of the cell lines, KOPN-8 and NOMO-1, were thoroughly characterized to understand the mechanisms involved in pinometostat resistance. Unlike many other targeted therapies, resistance does not appear to be achieved through drug-induced selection of mutations of the target itself. Instead, we identified both drug efflux transporter dependent and independent mechanisms of resistance to pinometostat. In KOPN-8 TER cells, increased expression of the drug efflux transporter ABCB1 (P-glycoprotein, MDR1) was the primary mechanism of drug resistance. In contrast, resistance in NOMO-1 cells occurs through a mechanism other than upregulation of a specific efflux pump. RNA-seq analysis performed on both parental and resistant KOPN-8 and NOMO-1 cell lines supported two unique candidate pathway mechanisms that may explain the pinometostat resistance observed in these cell lines. These results are the first demonstration of TER models of the DOT1L inhibitor pinometostat and may provide useful tools for investigating clinical resistance.

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Section: Hypothesis Generation and Testing Of Nomo-1 Mechanism Of Resmentioning

confidence: 99%

“…Pinometostat was made by Epizyme (38). Proliferation assays with combination agents valspodar (PSC 833, R&D Systems), trametinib (Selleck Chem), GDC-0994 (Selleck Chem), and dabrafenib (Selleck Chem) were completed with the above conditions (39)(40)(41)(42).…”

Section: Cell Culture and Analysis Of Cell Proliferation And Viabilitymentioning

confidence: 99%

Mechanisms of Pinometostat (EPZ-5676) Treatment–Emergent Resistance in MLL-Rearranged Leukemia

Campbell

Haladyna

Drubin

et al. 2017

Molecular Cancer Therapeutics

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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].…”

Section: Discussionmentioning

confidence: 99%

“…This general inhibition of ERK substrate phosphorylation thus underlies the therapeutic efficacy, as well as toxicity and feedback reactivation, associated with inhibition of the pathway. Likewise, ATP-competitive inhibitors of ERK1/2 currently in development [12, 13] are expected to generally block substrate phosphorylation and thus suffer from the same shortcomings. Theoretically, selective blockade of ERK activity could overcome these limitations, for example by inhibiting phosphorylation of oncogenic substrates while sparing substrates important for tissue homeostasis or those involved in feedback inhibition.…”

Section: Introductionmentioning

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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“…ERK1 and ERK2 are highly homologous (84% identical) and most of the ERK inhibitors including G994 and S984, displayed similar inhibitory potency toward ERK1 and ERK2 (30,56). Therefore, it is expected that these inhibitors bind to ERK1 and ERK2 in a similar manner.…”

Section: Structural Analysis Of Erki-resistant Mutantsmentioning

confidence: 98%

ERK Mutations and Amplification Confer Resistance to ERK-Inhibitor Therapy

Jaiswal¹,

Durinck²,

Stawiski³

et al. 2018

Clinical Cancer Research

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Results:We have identified mutations in ERK1/2, amplification and overexpression of ERK2, and overexpression of EGFR/ERBB2 as mechanisms of acquired resistance. Structural analysis of ERK showed that specific compounds that induced on-target ERK mutations were impaired in their ability to bind mutant ERK. We show that in addition to MEK inhibitor, ERBB-receptor and PI3K/mTOR pathway inhibitors are effective in overcoming ERK-inhibitor resistance.Conclusions: These findings suggest that combination therapy with MEK or ERBB-receptor or PI3K/mTOR and ERK inhibitors may be an effective strategy for managing the emergence of resistance in the clinic. Author Manuscript Published OnlineFirst on May 14, 2018; DOI: 10.1158/1078 3 Translational Relevance:Acquired resistance to targeted therapy is a major challenge. ERK inhibitors are under investigation for treatment of RAF/RAS mutated tumors or those resistant to BRAF/MEK inhibitors. Understanding the evolution of resistance to current ERK inhibitors will help guide in developing better inhibitors and also aid in identifying strategies for combination therapy that can overcome clinical resistance development.

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Discovery of (S)-1-(1-(4-Chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one (GDC-0994), an Extracellular Signal-Regulated Kinase 1/2 (ERK1/2) Inhibitor in Early Clinical Development

Cited by 135 publications

References 23 publications

Mechanisms of Pinometostat (EPZ-5676) Treatment–Emergent Resistance in MLL-Rearranged Leukemia

Mechanisms of Pinometostat (EPZ-5676) Treatment–Emergent Resistance in MLL-Rearranged Leukemia

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

ERK Mutations and Amplification Confer Resistance to ERK-Inhibitor Therapy

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