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Discovery of a potent, selective, and orally bioavailable pyridinyl-pyrimidine phthalazine aurora kinase inhibitor.

Cee VJ, Schenkel LB, Hodous BL, Deak HL, Nguyen HN, Olivieri PR, Romero K, Bak A, Be X, Bellon S, Bush TL, Cheng AC, Chung G, Coats S, Eden PM, Hanestad K, Gallant PL, Gu Y, Huang X, Kendall RL, Lin MH, Morrison MJ, Patel VF, Radinsky R, Rose PE, Ross S, Sun JR, Tang J, Zhao H, Payton M, Geuns-Meyer SD
J Med Chem 53 6368-77 (2010)
Cited: 9 times
EuropePMC logo PMID: 20684549

Abstract

The discovery of aurora kinases as essential regulators of cell division has led to intense interest in identifying small molecule aurora kinase inhibitors for the potential treatment of cancer. A high-throughput screening effort identified pyridinyl-pyrimidine 6a as a moderately potent dual inhibitor of aurora kinases -A and -B. Optimization of this hit resulted in an anthranilamide lead (6j) that possessed improved enzyme and cellular activity and exhibited a high level of kinase selectivity. However, this anthranilamide and subsequent analogues suffered from a lack of oral bioavailability. Converting the internally hydrogen-bonded six-membered pseudo-ring of the anthranilamide to a phthalazine (8a-b) led to a dramatic improvement in oral bioavailability (38-61%F) while maintaining the potency and selectivity characteristics of the anthranilamide series. In a COLO 205 tumor pharmacodynamic assay measuring phosphorylation of the aurora-B substrate histone H3 at serine 10 (p-histone H3), oral administration of 8b at 50 mg/kg demonstrated significant reduction in tumor p-histone H3 for at least 6 h.

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Articles citing this publication (7)

  1. Development of o-chlorophenyl substituted pyrimidines as exceptionally potent aurora kinase inhibitors. Lawrence HR, Martin MP, Luo Y, Pireddu R, Yang H, Gevariya H, Ozcan S, Zhu JY, Kendig R, Rodriguez M, Elias R, Cheng JQ, Sebti SM, Schonbrunn E, Lawrence NJ. J. Med. Chem. 55 7392-7416 (2012)
  2. Protozoan Parasite Growth Inhibitors Discovered by Cross-Screening Yield Potent Scaffolds for Lead Discovery. Devine W, Woodring JL, Swaminathan U, Amata E, Patel G, Erath J, Roncal NE, Lee PJ, Leed SE, Rodriguez A, Mensa-Wilmot K, Sciotti RJ, Pollastri MP. J. Med. Chem. 58 5522-5537 (2015)
  3. Polyphenols bearing cinnamaldehyde scaffold showing cell growth inhibitory effects on the cisplatin-resistant A2780/Cis ovarian cancer cells. Shin SY, Jung H, Ahn S, Hwang D, Yoon H, Hyun J, Yong Y, Cho HJ, Koh D, Lee YH, Lim Y. Bioorg. Med. Chem. 22 1809-1820 (2014)
  4. Benzochalcones bearing pyrazoline moieties show anti-colorectal cancer activities and selective inhibitory effects on aurora kinases. Shin SY, Yoon H, Hwang D, Ahn S, Kim DW, Koh D, Lee YH, Lim Y. Bioorg. Med. Chem. 21 7018-7024 (2013)
  5. Combined 3D-QSAR modeling and molecular docking studies on pyrrole-indolin-2-ones as Aurora A kinase inhibitors. Ai Y, Wang ST, Sun PH, Song FJ. Int J Mol Sci 12 1605-1624 (2011)
  6. Quantitative conformational profiling of kinase inhibitors reveals origins of selectivity for Aurora kinase activation states. Lake EW, Muretta JM, Thompson AR, Rasmussen DM, Majumdar A, Faber EB, Ruff EF, Thomas DD, Levinson NM. Proc. Natl. Acad. Sci. U.S.A. 115 E11894-E11903 (2018)
  7. Identification of Some Promising Heterocycles Useful in Treatment of Allergic Rhinitis: Virtual Screening, Pharmacophore Mapping, Molecular Docking, and Molecular Dynamics. Xiaopeng Sun, Belal A, Elanany MA, Alsantali RI, Alrooqi MM, Mohamed AR, Hasabelnaby S. Russ J Bioorg Chem 48 438-456 (2022)


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