3en5 Citations

Targeted polypharmacology: discovery of dual inhibitors of tyrosine and phosphoinositide kinases.

OpenAccess logo Nat. Chem. Biol. 4 691-9 (2008)
Related entries: 2v4l, 3en6, 3en7, 3en4, 3ene

Cited: 201 times
EuropePMC logo PMID: 18849971

Abstract

The clinical success of multitargeted kinase inhibitors has stimulated efforts to identify promiscuous drugs with optimal selectivity profiles. It remains unclear to what extent such drugs can be rationally designed, particularly for combinations of targets that are structurally divergent. Here we report the systematic discovery of molecules that potently inhibit both tyrosine kinases and phosphatidylinositol-3-OH kinases, two protein families that are among the most intensely pursued cancer drug targets. Through iterative chemical synthesis, X-ray crystallography and kinome-level biochemical profiling, we identified compounds that inhibit a spectrum of new target combinations in these two families. Crystal structures revealed that the dual selectivity of these molecules is controlled by a hydrophobic pocket conserved in both enzyme classes and accessible through a rotatable bond in the drug skeleton. We show that one compound, PP121, blocks the proliferation of tumor cells by direct inhibition of oncogenic tyrosine kinases and phosphatidylinositol-3-OH kinases. These molecules demonstrate the feasibility of accessing a chemical space that intersects two families of oncogenes.

Reviews citing this publication (108)

  1. Targeting the phosphoinositide 3-kinase pathway in cancer. Liu P, Cheng H, Roberts TM, Zhao JJ. Nat Rev Drug Discov 8 627-644 (2009)
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  4. Regulation and function of mTOR signalling in T cell fate decisions. Chi H. Nat. Rev. Immunol. 12 325-338 (2012)
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  7. Selectivity and therapeutic inhibition of kinases: to be or not to be? Ghoreschi K, Laurence A, O'Shea JJ. Nat. Immunol. 10 356-360 (2009)
  8. Fibroblast activation and myofibroblast generation in obstructive nephropathy. Grande MT, López-Novoa JM. Nat Rev Nephrol 5 319-328 (2009)
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  11. A network medicine approach to human disease. Zanzoni A, Soler-López M, Aloy P. FEBS Lett. 583 1759-1765 (2009)
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  62. Multiple binding sites in the nicotinic acetylcholine receptors: An opportunity for polypharmacolgy. Iturriaga-Vásquez P, Alzate-Morales J, Bermudez I, Varas R, Reyes-Parada M. Pharmacol. Res. 101 9-17 (2015)
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  71. Predictive in silico off-target profiling in drug discovery. Schmidt F, Matter H, Hessler G, Czich A. Future Med Chem 6 295-317 (2014)
  72. mTOR inhibitors: changing landscape of endocrine-resistant breast cancer. Chumsri S, Sabnis G, Tkaczuk K, Brodie A. Future Oncol 10 443-456 (2014)
  73. Polypharmacology: drug discovery for the future. Reddy AS, Zhang S. Expert Rev Clin Pharmacol 6 41-47 (2013)
  74. Modulation of insulin-like growth factor-1 receptor and its signaling network for the treatment of cancer: current status and future perspectives. Jin M, Buck E, Mulvihill MJ. Oncol Rev 7 e3 (2013)
  75. A Drosophila approach to thyroid cancer therapeutics. Das TK, Cagan RL. Drug Discov Today Technol 10 e65-71 (2013)
  76. Furthering the design and the discovery of small molecule ATP-competitive mTOR inhibitors as an effective cancer treatment. Lv X, Ma X, Hu Y. Expert Opin Drug Discov 8 991-1012 (2013)
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  78. Network, nodes and nexus: systems approach to multitarget therapeutics. Murthy D, Attri KS, Gokhale RS. Curr. Opin. Biotechnol. 24 1129-1136 (2013)
  79. Targeting oncogenic and epigenetic survival pathways in lymphoma. Leslie LA, Younes A. Leuk. Lymphoma 54 2365-2376 (2013)
  80. Modular pharmacology: deciphering the interacting structural organization of the targeted networks. Wang Z, Wang YY. Drug Discov. Today 18 560-566 (2013)
  81. What general conclusions can we draw from kinase profiling data sets? Sutherland JJ, Gao C, Cahya S, Vieth M. Biochim. Biophys. Acta 1834 1425-1433 (2013)
  82. Novel computational approaches to polypharmacology as a means to define responses to individual drugs. Xie L, Xie L, Kinnings SL, Bourne PE. Annu. Rev. Pharmacol. Toxicol. 52 361-379 (2012)
  83. System-based drug discovery within the human kinome. Bamborough P. Expert Opin Drug Discov 7 1053-1070 (2012)
  84. Ligand-receptor interaction platforms and their applications for drug discovery. Fang Y. Expert Opin Drug Discov 7 969-988 (2012)
  85. Combinatorial drug therapy for cancer in the post-genomic era. Al-Lazikani B, Banerji U, Workman P. Nat. Biotechnol. 30 679-692 (2012)
  86. Regulation and function of mTOR signalling in T cell fate decisions. Chi H. Nat. Rev. Immunol. 12 325-338 (2012)
  87. From laptop to benchtop to bedside: structure-based drug design on protein targets. Chen L, Morrow JK, Tran HT, Phatak SS, Du-Cuny L, Zhang S. Curr. Pharm. Des. 18 1217-1239 (2012)
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  89. New insights into small-molecule inhibitors of Bcr-Abl. Schenone S, Bruno O, Radi M, Botta M. Med Res Rev 31 1-41 (2011)
  90. Progress in the preclinical discovery and clinical development of class I and dual class I/IV phosphoinositide 3-kinase (PI3K) inhibitors. Shuttleworth SJ, Silva FA, Cecil AR, Tomassi CD, Hill TJ, Raynaud FI, Clarke PA, Workman P. Curr. Med. Chem. 18 2686-2714 (2011)
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  94. Somatic mutations in PI3Kalpha: structural basis for enzyme activation and drug design. Gabelli SB, Mandelker D, Schmidt-Kittler O, Vogelstein B, Amzel LM. Biochim. Biophys. Acta 1804 533-540 (2010)
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  101. A network medicine approach to human disease. Zanzoni A, Soler-López M, Aloy P. FEBS Lett. 583 1759-1765 (2009)
  102. Navigating the network: signaling cross-talk in hematopoietic cells. Fraser ID, Germain RN. Nat. Immunol. 10 327-331 (2009)
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  104. Structure-based design of molecular cancer therapeutics. van Montfort RL, Workman P. Trends Biotechnol. 27 315-328 (2009)
  105. Fibroblast activation and myofibroblast generation in obstructive nephropathy. Grande MT, López-Novoa JM. Nat Rev Nephrol 5 319-328 (2009)
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  107. Predicting drug side-effects by chemical systems biology. Tatonetti NP, Liu T, Altman RB. Genome Biol. 10 238 (2009)
  108. Structure and organization of drug-target networks: insights from genomic approaches for drug discovery. Janga SC, Tzakos A. Mol Biosyst 5 1536-1548 (2009)

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