Discovery of a Potent, Injectable Inhibitor of Aurora Kinases Based on the Imidazo-[1,2-<i>a</i>]-Pyrazine Core

Yu, Tao; Tagat, Jayaram R.; Kerekes, Angela D.; Doll, Ronald J.; Zhang, Yonglian; Xiao, Yuan; Esposite, Sara; Belanger, David; Curran, Patrick J.; Mandal, Amit Kumar; Siddiqui, M. Arshad; Shih, Neng‐Yang; Basso, Andrea; Liu, Ming; Gray, Kimberly; Tevar, Seema; Jones, Jennifer; Lee, Suining; Liang, Lianzhu; Ponery, Samad; Smith, Elizabeth B.; Hruza, Alan; Voigt, Johannes H.; Ramanathan, Lata; Prosise, W.W.; Hu, Mengwei

doi:10.1021/ml100063w

Cited by 34 publications

(27 citation statements)

References 12 publications

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“…The 19 aurora-A and ligand complex structures with potent activity (IC 50 < 50 nM) were retrieved from the RCSB protein databank. We found that the 19 inhibitors used have a common scaffold in the form of an amine-based aromatic structure which includes quinazolines, imidazopyridines (3MYG [ 9 ]), imidazopyrazines (2X6D [ 10 ]), indazoles, pyrazoles (3FDN [ 3 ]), and substituted pyrimidines (2NP8 [ 11 ]). These amine moieties undergo a crucial H-bonding interaction with the residues around the A213 residue in aurora-A [ 2 ] and serve as criteria for filtering the numerous hits.…”

Section: Resultsmentioning

confidence: 99%

The Discovery of Aurora Kinase Inhibitor by Multi-Docking-Based Virtual Screening

Kim

Jung

Kang³

et al. 2014

IJMS

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We report the discovery of aurora kinase inhibitor using the fragment-based virtual screening by multi-docking strategy. Among a number of fragments collected from eMololecules, we found four fragment molecules showing potent activity (>50% at 100 μM) against aurora kinase. Based on the explored fragment scaffold, we selected two compounds in our synthesized library and validated the biological activity against Aurora kinase.

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Section: Resultsmentioning

confidence: 99%

The Discovery of Aurora Kinase Inhibitor by Multi-Docking-Based Virtual Screening

Kim

Jung

Kang³

et al. 2014

IJMS

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“…One explanation for their reticence to react is based on the presence of a basic heteroatom, which has the potential to ligate the palladium center, thus leading to catalyst inhibition or deactivation 2d. 3 Furthermore, despite interest in heterocycles containing a fused imidazole ring, such as imidazo[1,2‐ a ]pyridine,4a–c imidazo[1,2‐ b ]pyridazine,4d and imidazo[1,2‐ a ]pyrazine,4e the use of these types of substrates has not been extensively explored in cross‐coupling reactions.…”

Section: Ligand Effects In the Palladium‐catalyzed Amidation Of 4‐bromentioning

confidence: 99%

A Bulky Biaryl Phosphine Ligand Allows for Palladium‐Catalyzed Amidation of Five‐Membered Heterocycles as Electrophiles

Buchwald

2012

Angewandte Chemie

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Palladium-catalyzed amidation of five-membered heterocyclic bromides that contain multiple heteroatoms was achieved for the first time using the Pd/1 catalyst system. This system allows for efficient access to N-arylated imidazoles, pyrazoles, thiazoles, pyrroles, and thiophenes in moderate to excellent yield. Experimental results and DFT calculations point to the need for electron-rich and especially sterically demanding biaryl phosphine ligand to promote these difficult cross-coupling reactions.

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“…1), with activity against AURKA (IC 50 ≤4 nM) and AURKB (IC 50 ≤13 nM) [15], is currently in preclinical development. While there was one previous pharmacokinetic (PK) study done via IV injection [15], none provide data for oral bioavailability. Further, there is no published bioanalytical assay available to quantitate SCH-1473759.…”

Section: Introductionmentioning

confidence: 99%

A simple and rapid UHPLC–MS/MS method for the quantitation of the dual aurora kinase A/B inhibitor SCH-1473759 in murine plasma

Filho

Peer

Nguyen

et al. 2017

Journal of Pharmaceutical and Biomedical Analysis

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The Aurora kinase family facilitates cell division through various processes and is overexpressed in a wide variety of human cancers, leading to aneuploidy. For that reason, these enzymes are currently targets of a rising class of anticancer drugs, with some molecules already in therapeutic use. In this study, a new UHPLC-MS/MS method was developed and validated to quantitate a new pan Aurora kinase inhibitor still in preclinical development, SCH-1473759. This bioanalytical method employed a liquid-liquid extraction from plasma using ethyl acetate before evaporation. Calibration range encompassed 0.5-2500ng/mL. The inter- and intra-day accuracy and precision were assessed over five quality control levels; all within limits required by the FDA guidelines. Assay applicability was demonstrated in a first-in-animals study with oral administration, where the maximum plasma concentration (34ng/mL) occurred at 1h, the half-life (1h) was consistent with a previous IV study, and oral bioavailability was poor (F=0.002).

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Discovery of a Potent, Injectable Inhibitor of Aurora Kinases Based on the Imidazo-[1,2-a]-Pyrazine Core

Cited by 34 publications

References 12 publications

The Discovery of Aurora Kinase Inhibitor by Multi-Docking-Based Virtual Screening

The Discovery of Aurora Kinase Inhibitor by Multi-Docking-Based Virtual Screening

A Bulky Biaryl Phosphine Ligand Allows for Palladium‐Catalyzed Amidation of Five‐Membered Heterocycles as Electrophiles

A simple and rapid UHPLC–MS/MS method for the quantitation of the dual aurora kinase A/B inhibitor SCH-1473759 in murine plasma

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