The Human Kinome Targeted by FDA Approved Multi-Target Drugs and Combination Products: A Comparative Study from the Drug-Target Interaction Network Perspective

PLoS One. 2016 Nov 9;11(11):e0165737. doi: 10.1371/journal.pone.0165737. eCollection 2016.

Abstract

The human kinome is one of the most productive classes of drug target, and there is emerging necessity for treating complex diseases by means of polypharmacology (multi-target drugs and combination products). However, the advantages of the multi-target drugs and the combination products are still under debate. A comparative analysis between FDA approved multi-target drugs and combination products, targeting the human kinome, was conducted by mapping targets onto the phylogenetic tree of the human kinome. The approach of network medicine illustrating the drug-target interactions was applied to identify popular targets of multi-target drugs and combination products. As identified, the multi-target drugs tended to inhibit target pairs in the human kinome, especially the receptor tyrosine kinase family, while the combination products were able to against targets of distant homology relationship. This finding asked for choosing the combination products as a better solution for designing drugs aiming at targets of distant homology relationship. Moreover, sub-networks of drug-target interactions in specific disease were generated, and mechanisms shared by multi-target drugs and combination products were identified. In conclusion, this study performed an analysis between approved multi-target drugs and combination products against the human kinome, which could assist the discovery of next generation polypharmacology.

Publication types

  • Comparative Study

MeSH terms

  • Amino Acid Sequence
  • Antineoplastic Agents / therapeutic use*
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / enzymology
  • Breast Neoplasms / genetics
  • Breast Neoplasms / pathology
  • Drug Approval / legislation & jurisprudence
  • Drug Combinations
  • Drug Interactions
  • Female
  • Gene Expression
  • Humans
  • Leukemia / drug therapy*
  • Leukemia / enzymology
  • Leukemia / genetics
  • Leukemia / pathology
  • Lymphoma / drug therapy*
  • Lymphoma / enzymology
  • Lymphoma / genetics
  • Lymphoma / pathology
  • Male
  • Molecular Targeted Therapy
  • Phylogeny
  • Polypharmacology
  • Protein Kinase Inhibitors / therapeutic use*
  • Protein Kinases / classification
  • Protein Kinases / genetics*
  • Protein Kinases / metabolism
  • Sequence Alignment
  • Sequence Homology, Amino Acid
  • United States
  • United States Food and Drug Administration / legislation & jurisprudence

Substances

  • Antineoplastic Agents
  • Drug Combinations
  • Protein Kinase Inhibitors
  • Protein Kinases

Grant support

This work was funded by the research support of National Natural Science Foundation of China (81202459, 21505009); by the Chongqing Graduate Student Research Innovation Project (CYB14027); and by Fundamental Research Funds for the Central Universities (CDJZR14468801, CDJKXB14011, 2015CDJXY).