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Tong Y, Torrent M, Florjancic AS, et al. Pyrimidine-based tricyclic molecules as potent and orally efficacious inhibitors of wee1 kinase. ACS Med Chem Lett. 2014;6(1):58-62doi: 10.1021/ml5002745.
Tong, Y., Torrent, M., Florjancic, A. S., Bromberg, K. D., Buchanan, F. G., Ferguson, D. C., Johnson, E. F., Lasko, L. M., Maag, D., Merta, P. J., Olson, A. M., Osterling, D. J., Soni, N., Shoemaker, A. R., & Penning, T. D. (2015). Pyrimidine-based tricyclic molecules as potent and orally efficacious inhibitors of wee1 kinase. ACS medicinal chemistry letters, 6(1), 58-62. https://doi.org/10.1021/ml5002745
Tong, Yunsong, et al. "Pyrimidine-based tricyclic molecules as potent and orally efficacious inhibitors of wee1 kinase." ACS medicinal chemistry letters vol. 6,1 (2015): 58-62. doi: https://doi.org/10.1021/ml5002745
Tong Y, Torrent M, Florjancic AS, Bromberg KD, Buchanan FG, Ferguson DC, Johnson EF, Lasko LM, Maag D, Merta PJ, Olson AM, Osterling DJ, Soni N, Shoemaker AR, Penning TD. Pyrimidine-based tricyclic molecules as potent and orally efficacious inhibitors of wee1 kinase. ACS Med Chem Lett. 2014 Aug 06;6(1):58-62. doi: 10.1021/ml5002745. eCollection 2015 Jan 08. PMID: 25589931; PMCID: PMC4291713.
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ACS Med Chem Lett. 2014 Aug 06;6(1):58-62. doi: 10.1021/ml5002745. eCollection 2015 Jan 08.

Pyrimidine-based tricyclic molecules as potent and orally efficacious inhibitors of wee1 kinase.

ACS medicinal chemistry letters

Yunsong Tong, Maricel Torrent, Alan S Florjancic, Kenneth D Bromberg, Fritz G Buchanan, Debra C Ferguson, Eric F Johnson, Loren M Lasko, David Maag, Philip J Merta, Amanda M Olson, Donald J Osterling, Nirupama Soni, Alexander R Shoemaker, Thomas D Penning

Affiliations

  1. Cancer Research, Molecular Modeling, Pharmacology, and High Throughput Biology, Research and Development, AbbVie , 1 North Waukegan Road, North Chicago, Illinois 60064-6114, United States.

PMID: 25589931 PMCID: PMC4291713 DOI: 10.1021/ml5002745

Abstract

Aided by molecular modeling, compounds with a pyrimidine-based tricyclic scaffold were designed and confirmed to inhibit Wee1 kinase. Structure-activity studies identified key pharmacophores at the aminoaryl and halo-benzene regions responsible for binding affinity with sub-nM K i values. The potent inhibitors demonstrated sub-μM activities in both functional and mechanism-based cellular assays and also possessed desirable pharmacokinetic profiles. The lead molecule, 31, showed oral efficacy in potentiating the antiproliferative activity of irinotecan, a cytotoxic agent, in a NCI-H1299 mouse xenograft model.

Keywords: Wee1 kinase inhibitors; antitumor

References

  1. Mol Cancer. 2009 Jun 08;8:34 - PubMed
  2. PLoS One. 2009;4(4):e5120 - PubMed
  3. Clin Cancer Res. 2011 Jul 1;17(13):4200-7 - PubMed
  4. Structure. 2005 Apr;13(4):541-50 - PubMed
  5. Eur J Med Chem. 2008 Jun;43(6):1276-96 - PubMed
  6. PLoS One. 2012;7(6):e38254 - PubMed
  7. Trends Mol Med. 2011 Feb;17 (2):88-96 - PubMed
  8. J Med Chem. 2006 Aug 10;49(16):4896-911 - PubMed
  9. Cancer Cell. 2010 Sep 14;18(3):244-57 - PubMed
  10. Biochim Biophys Acta. 2013 Dec;1836(2):227-35 - PubMed
  11. Cell Cycle. 2013 Oct 1;12(19):3159-64 - PubMed
  12. Science. 1992 Sep 25;257(5078):1955-7 - PubMed
  13. Curr Biol. 2004 Dec 14;14(23):2143-8 - PubMed
  14. Bioorg Med Chem Lett. 2005 Apr 1;15(7):1931-5 - PubMed

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