Discovery of <i>N</i>-(4-(3-(2-Aminopyrimidin-4-yl)pyridin-2-yloxy)phenyl)-4-(4-methylthiophen-2-yl)phthalazin-1-amine (AMG 900), A Highly Selective, Orally Bioavailable Inhibitor of Aurora Kinases with Activity against Multidrug-Resistant Cancer Cell Lines

Geuns‐Meyer, Stephanie; Cee, Victor J.; Deak, Holly L.; Du, Bingfan; Hodous, Brian L.; Nguyen, Hanh Nho; Olivieri, Philip R.; Schenkel, Laurie B.; Vaida, Karina R.; Andrews, Paul S.; Bak, Annette; Be, Xuhai; Beltran, Pedro J.; Bush, Tammy L.; Chaves, Mary; Chung, Grace; Dai, Yang; Eden, Patrick; Hanestad, Kelly; Huang, Liyue; Lin, Min-Hwa Jasmine; Tang, Jin; Ziegler, Beth; Radinsky, Robert; Kendall, Richard; Patel, Vinod F.; Payton, Marc

doi:10.1021/acs.jmedchem.5b00183

Cited by 42 publications

(15 citation statements)

References 57 publications

(148 reference statements)

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“…Given the vital role of the Aurora kinases in mitosis, the pursuit of an inhibitor is intense, and several are moving through clinical trials (50,51). Interestingly, a small molecule stabilizer of Fbxl2 levels enhanced the degradation of AurKB, resulting in mitotic arrest and apoptosis (48).…”

Section: Introductionmentioning

confidence: 99%

F-box protein interactions with the hallmark pathways in cancer

Randle

Laman

2016

Seminars in Cancer Biology

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F-box proteins (FBP) are the substrate specifying subunit of Skp1-Cul1-FBP (SCF)-type E3 ubiquitin ligases and are responsible for directing the ubiquitination of numerous proteins essential for cellular function. Due to their ability to regulate the expression and activity of oncogenes and tumour suppressor genes, FBPs themselves play important roles in cancer development and progression. In this review, we provide a comprehensive overview of FBPs and their targets in relation to their interaction with the hallmarks of cancer cell biology, including the regulation of proliferation, epigenetics, migration and invasion, metabolism, angiogenesis, cell death and DNA damage responses. Each cancer hallmark is revealed to have multiple FBPs which converge on common signalling hubs or response pathways. We also highlight the complex regulatory interplay between SCF-type ligases and other ubiquitin ligases. We suggest six highly interconnected FBPs affecting multiple cancer hallmarks, which may prove sensible candidates for therapeutic intervention.

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Section: Introductionmentioning

confidence: 99%

F-box protein interactions with the hallmark pathways in cancer

Randle

Laman

2016

Seminars in Cancer Biology

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“…AMG 900 was engineered to have a high specificity for both of the target aurora kinases while evading the ATP‐binding cassette transporters, to have efficacy in multiple tumor xenograft models at reasonable doses, and to have predicted human pharmacokinetic properties that would provide adequate target coverage . Aurora B phosphorylates histone H3 on serine 10 during mitosis; hence the inhibition of pHH3 observed in this study suggests on‐target modulation of aurora kinase B by AMG 900.…”

Section: Discussionmentioning

confidence: 87%

A phase 1 study of AMG 900, an orally administered pan‐aurora kinase inhibitor, in adult patients with acute myeloid leukemia

et al. 2017

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Aurora kinases are involved in the pathophysiology of several cancers including acute myeloid leukemia (AML). In this phase 1 study, we investigated the safety and efficacy of AMG 900, an orally administered, highly potent, selective, small-molecule inhibitor of both Aurora kinase A and B, in patients with AML. Patients with pathologically documented AML who either declined standard treatments or had relapsed from or were refractory to previous therapies were enrolled. Two every-2-week dose-escalation schedules using a modified 3 + 3 + 3 design were evaluated AMG 900 given daily for 4 days with 10 days off (4/10 schedule), and AMG 900 given daily for 7 days with 7 days off (7/7 schedule). Thirty-five patients were enrolled at 9 different dose levels: 22 patients on the 4/10 schedule (doses from 15 to 100 mg daily), and 13 patients on the 7/7 schedule (doses from 30 to 50 mg daily). Both schedules were tolerated; nausea (31%), diarrhea (29%), febrile neutropenia (29%), and fatigue (23%) were the most common treatment-related adverse events. Three patients (9%) achieved complete response with incomplete count recovery. Patients with higher baseline expression of a set of specific pathway-related genes (BIRC5, AURKA, TTK, CDC2, and CCNB1) were more likely to respond in an exploratory biomarker analysis. AMG 900 was tolerated in a general AML population, and pathway-specific biomarkers identified a potential target population. Future research efforts will be directed toward further exploration of biomarkers of response and combination of AMG 900 with other anticancer agents.

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“…Of some interest are the preclinical observations showing the ability of different Aurora kinase inhibitors to have additive or synergist effects when combined with other anticancer therapies [109,110]. At example, among the pan-Aurora kinase inhibitors, the AMG-900 in combination with the HDAC (histone deacetylase) inhibitor vorinostat has been shown to synergistically reduce proliferation and survival of medulloblastoma and prostate cancer-derived cell lines [111,112]. Similarly, the SNS-314 has been shown to possess additive inhibitory effects on the HCT 116 cell line when combined with either carboplatin, gemcitabine, 5-FU, daunomycin, docetaxel, or vincristine [113].…”

Section: Aurora Kinase Inhibitorsmentioning

confidence: 99%

Aurora Kinases: New Molecular Targets for the Therapy of Aggressive Thyroid Cancers

Baldini¹,

Tuccilli²,

Sorrenti³

et al. 2016

Anti-Cancer Drugs - Nature, Synthesis and Cell

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Epithelial thyroid carcinomas (TC) account for more than 90% of all endocrine malignancies and represent one of the most frequent cancers in women. They include the well-differentiated TC (DTC), comprising the papillary (PTC) and follicular (FTC) histotypes, the poorly differentiated (PDTC), and the undifferentiated or anaplastic TC (ATC). Both PDTC and ATC are aggressive human neoplasms with a dire prognosis due to the absence of effective therapies, which makes mandatory the identification of novel therapeutic strategies. Intrinsic chromosomal instability (CIN, an increased rate of gain or losses of chromosomes during cell division) is a common feature of solid tumors and represents a major driving force in thyroid cancer progression, thought to be responsible for the acquisition by malignant cells of novel functional capabilities. Different mitotic kinases, whose expression or function has been found altered in human cancer tissues, are major drivers of thyroid tumor aneuploidy. Among these are the three members of the Aurora family (Aurora-A, Aurora-B and Aurora-C), serine/threonine kinases that regulate multiple aspects of chromosome segregation and cytokinesis. Over the last few years, several small molecule inhibitors targeting Aurora kinases were developed with promising antitumor effects in preclinical and clinical studies against different human cancers, including TC. Here, we will focus on the Aurora mitotic functions in normal cells; we shall then describe the main implications of their overexpression in the onset of genetic instability and aneuploidy. We will finally describe the consequences of Aurora kinase inhibition on TC cell growth and tumorigenicity.

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Discovery of N-(4-(3-(2-Aminopyrimidin-4-yl)pyridin-2-yloxy)phenyl)-4-(4-methylthiophen-2-yl)phthalazin-1-amine (AMG 900), A Highly Selective, Orally Bioavailable Inhibitor of Aurora Kinases with Activity against Multidrug-Resistant Cancer Cell Lines

Cited by 42 publications

References 57 publications

F-box protein interactions with the hallmark pathways in cancer

F-box protein interactions with the hallmark pathways in cancer

A phase 1 study of AMG 900, an orally administered pan‐aurora kinase inhibitor, in adult patients with acute myeloid leukemia

Aurora Kinases: New Molecular Targets for the Therapy of Aggressive Thyroid Cancers

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