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Li L, Li J, Khanna M, et al. Docking Small Molecules to Predicted Off-Targets of the Cancer Drug Erlotinib Leads to Inhibitors of Lung Cancer Cell Proliferation with Suitable In vitro Pharmacokinetic Properties. ACS Med Chem Lett. 2010;1(5):229-233doi: 10.1021/ml100031a.
Li, L., Li, J., Khanna, M., Jo, I., Baird, J. P., & Meroueh, S. O. (2010). Docking Small Molecules to Predicted Off-Targets of the Cancer Drug Erlotinib Leads to Inhibitors of Lung Cancer Cell Proliferation with Suitable In vitro Pharmacokinetic Properties. ACS medicinal chemistry letters, 1(5), 229-233. https://doi.org/10.1021/ml100031a
Li, Liwei, et al. "Docking Small Molecules to Predicted Off-Targets of the Cancer Drug Erlotinib Leads to Inhibitors of Lung Cancer Cell Proliferation with Suitable In vitro Pharmacokinetic Properties." ACS medicinal chemistry letters vol. 1,5 (2010): 229-233. doi: https://doi.org/10.1021/ml100031a
Li L, Li J, Khanna M, Jo I, Baird JP, Meroueh SO. Docking Small Molecules to Predicted Off-Targets of the Cancer Drug Erlotinib Leads to Inhibitors of Lung Cancer Cell Proliferation with Suitable In vitro Pharmacokinetic Properties. ACS Med Chem Lett. 2010 Aug 12;1(5):229-233. doi: 10.1021/ml100031a. PMID: 20824148; PMCID: PMC2931832.
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ACS Med Chem Lett. 2010 Aug 12;1(5):229-233. doi: 10.1021/ml100031a.

Docking Small Molecules to Predicted Off-Targets of the Cancer Drug Erlotinib Leads to Inhibitors of Lung Cancer Cell Proliferation with Suitable In vitro Pharmacokinetic Properties.

ACS medicinal chemistry letters

Liwei Li, Jing Li, May Khanna, Inha Jo, Jason P Baird, Samy O Meroueh

Affiliations

  1. Department of Biochemistry and Molecular Biology, Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, and Department of Chemistry and Chemical Biology, Indiana University Purdue University Indianapolis.

PMID: 20824148 PMCID: PMC2931832 DOI: 10.1021/ml100031a

Abstract

In an effort to develop a rational approach to identify anti-cancer agents with selective polypharmacology, we mine millions of docked protein-ligand complexes involving more than a thousand cancer targets from multiple signaling pathways to identify new structural templates for proven pharmacophores. Our method combines Support Vector Machine-based scoring to enrich the initial library of 1,592 molecules, with a fingerprint-based search for molecules that have the same binding profile as the EGFR kinase inhibitor erlotinib. Twelve new compounds were identified. In vitro activity assays revealed that three inhibited EGFR with IC(50) values ranging from 250 nM to 200 µM. Additional in vitro studies with hERG, CYP450, DNA and cell culture-based assays further compared their properties to erlotinib. One compound combined suitable pharmacokinetic properties while closely mimicking the binding profile of erlotinib. The compound also inhibited H1299 and H460 tumor cell proliferation. The other two compounds shared some of the binding profile of erlotinib, and one gave the most potent inhibition of tumor cell growth. Interestingly, among the compounds that had not shown inhibition of EGFR, four blocked H1299 and H460 proliferation, one potently with IC(50) values near 1 µM. This compound was from the menogaril family, which reached Phase II clinical trial for the treatment of lymphomas. This suggests that our computational approach comparing binding profile may have favored molecules with anti-cancer properties like erlotinib.

References

  1. Mol Cell Proteomics. 2008 Oct;7(10):2048-60 - PubMed
  2. J Med Chem. 1968 Mar;11(2):387-8 - PubMed
  3. Cancer Res. 1957 Jul;17(6):579-96 - PubMed
  4. Nature. 2010 Jan 14;463(7278):184-90 - PubMed
  5. Chem Pharm Bull (Tokyo). 1982 May;30(5):1609-17 - PubMed
  6. Anticancer Res. 1992 Nov-Dec;12(6B):1953-6 - PubMed
  7. Biosystems. 2006 Feb-Mar;83(2-3):81-90 - PubMed
  8. N Engl J Med. 2005 Jul 14;353(2):123-32 - PubMed
  9. Invest New Drugs. 1999;17(2):169-72 - PubMed
  10. Chem Res Toxicol. 2001 Jun;14(6):611-50 - PubMed
  11. Trends Pharmacol Sci. 2008 Feb;29(2):62-71 - PubMed
  12. Nucleic Acids Res. 2010 Jan;38(Database issue):D765-73 - PubMed
  13. Cell. 2001 Feb 23;104(4):569-80 - PubMed
  14. J Pharmacobiodyn. 1988 Sep;11(9):630-5 - PubMed

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