Skip to main content

Rethinking Drug Discovery and Targeting After the Genomic Revolution

  • Chapter
  • First Online:
  • 704 Accesses

Abstract

The study of the entire genome provides for a complete and better understanding of functional relationship of different genes, genes coding for protein and other regulating sequences, as phenotypic expression is a complex interplay of these and much more. The genomic revolution, in its practically applicable form, is yet to arrive. This genomic sequence information for various organisms, including humans, is now influencing drug discovery which provides opportunity for researchers to develop new drugs/medicines. Major challenges in new drug discovery are to identify targets that are essential for the organism to survive. Several latest technologies have allowed us to understand the mechanisms of disease with respect to biological system concepts, and therefore therapeutic intervention has been developed using informative database and technologies. Therefore, with developing therapeutic interventions, it is imperative for pharmaceutical researchers to rethink about new drug discovery and targeting employing information obtained from the genomic revolution. The chapter is summarized with an outline on the brief introduction on genomic revolution followed by changing scenario in drug discovery and targeting and paradigm shift in the treatment of certain major conditions such as cancer, cardiovascular diseases and tuberculosis in postgenomic era.

This is a preview of subscription content, log in via an institution.

Buying options

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

References

  1. Bishop WE, Clarke DP, Travis CC (2001) The genomic revolution: what does it mean for risk assessment? Risk Anal 21(6):983–987

    Article  CAS  PubMed  Google Scholar 

  2. Berman DM, Bosenberg MW, Orwant RL, Thurberg BL, Draetta GF, Fletcher CDM, Loda M (2012) Investigative pathology: leading the post-genomic revolution. Lab Investig 92:4–8

    Article  PubMed  Google Scholar 

  3. Collins F (2010) Has the revolution arrived? Nature 464:674–675

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Dopazo J (2014) Genomics and transcriptomics in drug discovery. Drug Discov Today 19(2):126–132

    Article  CAS  PubMed  Google Scholar 

  5. Hartwell LH, Hopfield JJ, Leibler S, Murray AW (1999) From molecular to modular cell biology. Nature 402:C47–C52

    Article  CAS  PubMed  Google Scholar 

  6. Reuter JA, Spacek D, Snyder MP (2015) High-throughput sequencing technologies. Molecular Cell 58(4):586–597

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Keim B (2010) 10 Years on, The genome revolution is only just beginning. http://wired.com/2010/03/genome-at-10/

  8. Chivers T (2014) Genomics the revolution that’s transforming medicine. http://www.telegraph.co.uk/news/science/science-news/11309154/Genomics-the-revolution-that-transforming-medicine.html

  9. Hofker MH, Wijmenga JFC (2014) The genome revolution and its role in understanding complex diseases. Biochim Biophys Acta 1842(10):1889–1895

    Article  CAS  PubMed  Google Scholar 

  10. Parkinson T (2002) The impact of genomics on anti-infectives drug discovery and development. Trends Microbiol 10(10):S22–S26

    Article  CAS  PubMed  Google Scholar 

  11. Kola I, Landis J (2004) Can the pharmaceutical industry reduce attrition rates? Nat Rev Drug Discov 3:711–715

    Article  CAS  PubMed  Google Scholar 

  12. Chiang SL, Mekalanos JJ, Holden DW (1999) In vivo genetic analysis of bacterial virulence. Annu Rev Microbiol 53:129–154

    Article  CAS  PubMed  Google Scholar 

  13. Capecchi B, Serruto D, AduBobie J, Rappuoli R, Pizza M (2004) The genome revolution in vaccine research. Curr Issues Mol Biol 6:17–28

    PubMed  CAS  Google Scholar 

  14. Chanda SK, Caldwell JS (2003) Fulfilling the promise: drug discovery in the post-genomic era. Drug Discov Today 8(4):168–174

    Article  CAS  PubMed  Google Scholar 

  15. Raczniak G, Ibba M, Söll D (2001) Genomics-based identification of targets in pathogenic bacteria for potential therapeutic and diagnostic use. Toxicology 160:181–189

    Article  CAS  PubMed  Google Scholar 

  16. Murphy MP (2000) Current pharmacogenomic approaches to drug development. Pharmacogenomics 1(2):115–123

    Article  CAS  PubMed  Google Scholar 

  17. Murphy MP (2000) Pharmacogenomics a new paradigm for drug development. Drug Discov World Fall 1:23–32

    Google Scholar 

  18. Katsios C, Roukos DH (2010) Individual genomes and personalized medicine: life diversity and complexity. Pers Med 7(4):347–350

    Article  CAS  Google Scholar 

  19. Roederer MW (2009) Cytochrome P450 enzymes and genotype-guided drug therapy. Curr Opin Mol Ther 11(6):632–640

    PubMed  CAS  Google Scholar 

  20. Mok TS et al (2009) Gefitinib or carboplatin–paclitaxel in pulmonary adenocarcinoma. N Engl J Med 361:947–957

    Article  CAS  PubMed  Google Scholar 

  21. Paez JG, Janne PA et al (2004) EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 304(5676):1497–1500

    Article  CAS  PubMed  Google Scholar 

  22. O’Brien SG, Guilhot F, Larson RA et al (2003) Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med 348:994–1004

    Article  PubMed  Google Scholar 

  23. Druker BJ, Guilhot F, O’Brien SG et al (2006) Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med 355:2408–2417

    Article  CAS  PubMed  Google Scholar 

  24. Hirota S, Isozaki K, Moriyama Y et al (1998) Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science 279:577–580

    Article  CAS  PubMed  Google Scholar 

  25. Demetri GD, von Mehren M, Blanke CD et al (2002) Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med 347:472–480

    Article  CAS  PubMed  Google Scholar 

  26. DeMatteo RP, Lewis JJ, Leung D, Mudan SS, Woodruff JM, Brennan MF (2000) Two hundred gastrointestinal stromal tumors: recurrence patterns and prognostic factors for survival. Ann Surg 231:51–58

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Sawyers CL (2002) Rational therapeutic intervention in cancer: kinases as drug targets. Curr Opin Genet Dev 12(1):111–115

    Article  CAS  PubMed  Google Scholar 

  28. Singh SB, Lingham RB (2002) Current progress on farnesyl protein transferase inhibitors. Curr Opin Drug Discov Devel 5:225–244

    PubMed  CAS  Google Scholar 

  29. Adjei A (2001) Blocking oncogenic Ras signaling for cancer therapy. J Natl Cancer Inst 93(14):1062–1074

    Article  CAS  PubMed  Google Scholar 

  30. Stamenkovic I (2000) Matrix metalloproteinases in tumor invasion and metastasis. Semin Cancer Biol 10:415–433

    Article  CAS  PubMed  Google Scholar 

  31. Ramnath N, Creaven PJ (2004) Matrix metalloproteinase inhibitors. Curr Oncol Rep 6:96–102

    Article  PubMed  Google Scholar 

  32. Van Cutsem E, van de Velde H, Karasek P, Oettle H, Vervenne WL, Szawlowski A, Schoffski P, Post S, Verslype C, Neumann H, Safran H, Humblet Y, Perez Ruixo J, Ma Y, Von Hoff DJ (2004) Phase III trial of gemcitabine plus tipifarnib compared with gemcitabine plus placebo in advanced pancreatic cancer. Clin Oncol 22:1430–1438

    Article  CAS  Google Scholar 

  33. Zonnenberg BA, Groenewegen G, Janus TJ, Leahy TW, Humerickhouse RA, Isaacson JD, Car RA, Voest E (2003) Phase I dose-escalation study of the safety and pharmacokinetics of atrasentan: an endothelin receptor antagonist for refractory prostate cancer. Clin Cancer Res 9:2965

    PubMed  CAS  Google Scholar 

  34. Lee D (2003) Clinical trials of atrasentan in hormone-refractory prostate cancer. Clin Prostate Cancer 2(2):84–86

    Article  CAS  PubMed  Google Scholar 

  35. Ferrara N (2005) VEGF as a therapeutic target in cancer. Oncology 69(3):11–16

    Article  CAS  PubMed  Google Scholar 

  36. Singh SK, Vobbalareddy S, Shivaramakrishna S, Krishnamaraju A, Abdul Rajjak S, Casturi SR, Akhila V, Rao YK (2004) Methanesulfonamide group at position-4 of the C-5-phenyl ring of 1,5-diarylpyrazole affords a potent class of cyclooxygenase-2 (COX-2) inhibitors. Bioorg Med Chem Lett 14:1683–1688

    Article  CAS  PubMed  Google Scholar 

  37. Zarghi A, Arfaei S (2011) Selective COX-2 inhibitors: a review of their structure-activity relationships. Iran J Pharm Res 10(4):655–683

    PubMed  PubMed Central  CAS  Google Scholar 

  38. Jhaveri K et al (2012) A phase I dose-escalation trial of trastuzumab and alvespimycin hydrochloride (KOS- 1022; 17 DMAG) in the treatment of advanced solid tumors. Clin Cancer Res 18:5090–5098

    Article  CAS  PubMed  Google Scholar 

  39. National Cancer Institute (2014) Clinical trials search. http://www.cancer.gov/clinicaltrials/search/results?protocolsearchid=12897579

  40. Plump AS, Lum PY (2009) Genomics and cardiovascular drug development. J Am Coll Cardiol 53(13):1089–1100

    Article  CAS  PubMed  Google Scholar 

  41. Zycher B, DiMasi JA, Milne CP, The Truth about Drug Innovation (2008) Thirty-five summary case histories on private sector contributions to pharmaceutical science. Medical progress report. Manhattan Institute, New York

    Google Scholar 

  42. Scriabine A (2007) Challenges for cardiovascular drug research. Cardiovasc Drug Rev 259:205–220

    Article  Google Scholar 

  43. Zadelaar S, Kleemann R, Verschuren L et al (2007) Mouse models for atherosclerosis and pharmaceutical modifiers. Arterioscler Thromb Vasc Biol 27:1706–1721

    Article  CAS  PubMed  Google Scholar 

  44. Reardon CA, Getz GS (2001) Mouse models of atherosclerosis. Curr Opin Lipidol 12:167–173

    Article  CAS  PubMed  Google Scholar 

  45. Ganesh SK et al (2013) Genetics and genomics for the prevention and treatment of cardiovascular disease: update a scientific statement from the American Heart Association. Circulation 24(31):1–39

    Google Scholar 

  46. Arnett DK, Baird AE, Barkley RA, Basson CT, Boerwinkle E, Ganesh SK, Herrington DM, Hong Y, Jaquish C, McDermott DA, O’Donnell CJ (2007) Relevance of genetics and genomics for prevention and treatment of cardiovascular disease: a scientific statement from the American Heart Association Council on Epidemiology and Prevention, the Stroke Council, and the Functional Genomics and Translational Biology Interdisciplinary Working Group. Circulation 115:2878–2901

    Article  PubMed  Google Scholar 

  47. Singer JB, Lewitzky S, Leroy E, Yang F, Zhao X, Klickstein L, Wright TM, Meyer J, Paulding CA (2010) A genome-wide study identifies HLA alleles associated with lumiracoxib-related liver injury. Nat Genet 42:711–714

    Article  CAS  PubMed  Google Scholar 

  48. Pepe MS, Janes H, Longton G, Leisenring W, Newcomb P (2004) Limitations of the odds ratio in gauging the performance of a diagnostic, prognostic, or screening marker. Am J Epidemiol 159:882–890

    Article  PubMed  Google Scholar 

  49. Zhou K et al (2011) Common variants near ATM are associated with glycemic response to metformin in type 2 diabetes. Nat Genet 43:117–120

    Article  CAS  PubMed  Google Scholar 

  50. Yee SW, Chen L, Giacomini KM (2012) The role of ATM in response to metformin treatment and activation of AMPK. Nat Genet 44:359–360

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Hirschhorn JN, Daly MJ (2005) Genome-wide association studies for common diseases and complex traits. Nat Rev Genet 6:95–108

    Article  CAS  PubMed  Google Scholar 

  52. Bamshad MJ, Ng SB, Bigham AW, Tabor HK, Emond MJ, Nickerson DA, Shendure J (2011) Exome sequencing as a tool for mendelian disease gene discovery. Nat Rev Genet 12:745–755

    Article  CAS  PubMed  Google Scholar 

  53. McCarthy MI, Abecasis GR, Cardon LR, Goldstein DB, Little J, Ioannidis JP, Hirschhorn JN (2008) Genome-wide association studies for complex traits: consensus, uncertainty and challenges. Nat Rev Genet 9:356–369

    Article  CAS  PubMed  Google Scholar 

  54. Dewey FE, Pan S, Wheeler MT, Quake SR, Ashley EA (2012) DNA sequencing: clinical applications of new DNA sequencing technologies. Circulation 125:931–944

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Chakravarti A, Kapoor A (2012) Genetics and genomics in cardiovascular gene discovery. In: Hill JA, Olson EN (eds) Muscle: fundamental biology and mechanism of disease. Elsevier, Waltham, pp 231–259

    Chapter  Google Scholar 

  56. Mudd JO, Kass DA (2008) Tackling heart failure in the twenty-first century. Nature 451:919–928

    Article  CAS  PubMed  Google Scholar 

  57. Shah AM, Mann DL (2011) In search of new therapeutic targets and strategies for heart failure: recent advances in basic science. Lancet 378:704–712

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Azmi AS, Wang Z, Philip PA, Mohammad RM, Sarkar FH (2010) Proof of concept: network and systems biology approaches aid in the discovery of potent anticancer drug combinations. Mol Cancer Ther 9:3137–3144

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Roukos DH (2010) Novel clinico-genome network modeling for revolutionizing genotype-phenotype-based personalized cancer care. Expert Rev Mol Diagn 10:33–48

    Article  CAS  PubMed  Google Scholar 

  60. Ballell L et al (2013) Fueling open-source drug discovery: 177 small-molecule leads against tuberculosis. ChemMedChem 8:313–321

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Andries K et al (2005) A diarylquinoline drug active on the ATP synthase of Mycobacterium tuberculosis. Science 307(5707):223–227

    Article  CAS  PubMed  Google Scholar 

  62. Christophe T et al (2009) High content screening identifies decaprenyl-phosphoribose 2′ epimerase as a target for intracellular antimycobacterial inhibitors. PLoS Pathog 5(10):e1000645

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Pethe K et al (2013) Discovery of Q203, a potent clinical candidate for the treatment of tuberculosis. Nat Med 19:1157–1160

    Article  CAS  PubMed  Google Scholar 

  64. Abrahams KA et al (2012) Identification of novel imidazo[1,2-a]pyridine inhibitors targeting M. tuberculosis QcrB. PLoS One 7:e52951

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Protopopova M, Hanrahan C, Nikonenko B, Samala R, Chen P, Gearhart J, Einck L, Nacy CA (2005) Identification of a new antitubercular drug candidate, SQ109, from a combinatorial library of 1,2-ethylenediamines. J Antimicrob Chemother 56:968–974

    Article  CAS  PubMed  Google Scholar 

  66. Tahlan K et al (2012) SQ109 targets MmpL3, a membrane transporter of trehalosemonomycolate involved in mycolic acid donation to the cell wall core of Mycobacterium tuberculosis. Antimicrob Agents Chemother 56:1797–1809

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Wilson R et al (2013) Antituberculosis thiophenes define a requirement for Pks13 in mycolic acid biosynthesis. Nat Chem Biol 9(8):499–506

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Willand N et al (2009) Synthetic EthR inhibitors boost antituberculous activity of ethionamide. Nat Med 15:537–544

    Article  CAS  PubMed  Google Scholar 

  69. Bitter W et al (2009) Systematic genetic nomenclature for type VII secretion systems. PLoS Pathog 5(10):e1000507

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Simeone R, Bottai D, Brosch R (2009) ESX/type VII secretion systems and their role in host–pathogen interaction. Curr Opin Microbiol 12(1):4–10

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Viness Pillay .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2018 Springer Nature Singapore Pte Ltd.

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Chejara, D.R. et al. (2018). Rethinking Drug Discovery and Targeting After the Genomic Revolution. In: Pathak, Y. (eds) Genomics-Driven Healthcare. Adis, Singapore. https://doi.org/10.1007/978-981-10-7506-3_1

Download citation

Publish with us

Policies and ethics