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Receptor Tyrosine Kinase
- 1. Dr. Saurabh Patil JR-1 Guidedby: Dr. Shruti Bhide Receptor Tyrosine Kinase March 23, 2019
- 2. Overview 1. Clinical case 2.Receptor classification 3. ReceptorTyrosine Kinase 4. Structure 5. Activation & Signaling Pathway 6. Families of RTK 7. Manifest Patterns 8. Evolution /Timeline 9. Development & Pipeline 10.Challenges in drug developement
- 3. • 58 yearsold male • Routine employee check-up • No complaints • Incidental splenomegaly Your patient
- 4. Your patient RT PCRfor BCR ABL mRNA 70% Blasts 10%
- 5. Your patient RT PCRfor BCR ABL mRNA 70%
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- 10. Receptors Neuroscience. 2nd edition.Purves D,Augustine GJ, Fitzpatrick D, et al., editors. Sunderland (MA): Sinauer Associates; 2001.
- 11. Receptors Neuroscience. 2nd edition.Purves D,Augustine GJ, Fitzpatrick D, et al., editors. Sunderland (MA): Sinauer Associates; 2001.
- 12. Receptors Neuroscience. 2nd edition.Purves D,Augustine GJ, Fitzpatrick D, et al., editors. Sunderland (MA): Sinauer Associates; 2001.
- 13. Receptors Neuroscience. 2nd edition.Purves D,Augustine GJ, Fitzpatrick D, et al., editors. Sunderland (MA): Sinauer Associates; 2001.
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- 16. Receptors 1. ReceptorTyrosine Kinase 2.Receptor Serine / Threonine Kinase 3. Receptor Guanylyl Cyclases 4. Tyrosine-Kinase Associated Receptors 5. ReceptorTyrosine Phosphatases
- 17. Receptors 1. ReceptorTyrosine Kinase 2.Receptor Serine / Threonine Kinase 3. Receptor Guanylyl Cyclases 4. Tyrosine-Kinase Associated Receptors 5. ReceptorTyrosine Phosphatases
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- 20. ReceptorTyrosine Kinase KINASE P PP A P P A Target Target
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- 22. ReceptorTyrosine Kinase KINASE P PP A P P A Ty r Ty r Ty r
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- 38. Activation TETHERED STATE TeramuraY, Ichinose J,TakagiH, Nishida K,YanagidaT, SakoY. Single-molecule analysis of epidermal growth factor binding on the surface of living cells. EMBO J. 2006 Sep 20;25(18):4215–22.
- 39. Activation EXTENDED STATE TeramuraY, Ichinose J,TakagiH, Nishida K,YanagidaT, SakoY. Single-molecule analysis of epidermal growth factor binding on the surface of living cells. EMBO J. 2006 Sep 20;25(18):4215–22.
- 40. Activation PREDIMER STATE TeramuraY, Ichinose J,TakagiH, Nishida K,YanagidaT, SakoY. Single-molecule analysis of epidermal growth factor binding on the surface of living cells. EMBO J. 2006 Sep 20;25(18):4215–22.
- 41. Activation FLUCTUATIO N STATE TeramuraY, Ichinose J,TakagiH, Nishida K,YanagidaT, SakoY. Single-molecule analysis of epidermal growth factor binding on the surface of living cells. EMBO J. 2006 Sep 20;25(18):4215–22.
- 42. Activation KINETIC INTERMEDIAT E TeramuraY, Ichinose J,TakagiH, Nishida K,YanagidaT, SakoY. Single-molecule analysis of epidermal growth factor binding on the surface of living cells. EMBO J. 2006 Sep 20;25(18):4215–22.
- 43. Activation SIGNALING DIMER TeramuraY, Ichinose J,TakagiH, Nishida K,YanagidaT, SakoY. Single-molecule analysis of epidermal growth factor binding on the surface of living cells. EMBO J. 2006 Sep 20;25(18):4215–22.
- 44. Activation PREDIMER HubbardSR, MillerWT. Receptortyrosine kinases: mechanisms of activation and signaling. Curr Opin Cell Biol. 2007 Apr;19(2):117–23.
- 45. Activation C terminal N terminal Lobe interaction HubbardSR,MillerWT. Receptor tyrosine kinases: mechanisms of activation and signaling. Curr Opin Cell Biol. 2007 Apr;19(2):117–23.
- 46. Activation Kinase Activity HubbardSR, MillerWT. Receptortyrosine kinases: mechanisms of activation and signaling. Curr Opin Cell Biol. 2007 Apr;19(2):117–23.
- 47. How do weknow all this?
- 48. How do weknow all this? Gherardi E, Sandin S, Petoukhov MV, Finch J,Youles ME, Ofverstedt L-G, et al. Structural basis of hepatocyte growth factor/scatter factor and MET signalling. Proc Natl Acad Sci USA. 2006 Mar 14;103(11):4046–51.
- 49. How do weknow all this? Gherardi E, Sandin S, Petoukhov MV, Finch J,Youles ME, Ofverstedt L-G, et al. Structural basis of hepatocyte growth factor/scatter factor and MET signalling. Proc Natl Acad Sci USA. 2006 Mar 14;103(11):4046–51.
- 50. How do weknow all this? Gherardi E, Sandin S, Petoukhov MV, Finch J,Youles ME, Ofverstedt L-G, et al. Structural basis of hepatocyte growth factor/scatter factor and MET signalling. Proc Natl Acad Sci USA. 2006 Mar 14;103(11):4046–51.
- 51. How do weknow all this? Gherardi E, Sandin S, Petoukhov MV, Finch J,Youles ME, Ofverstedt L-G, et al. Structural basis of hepatocyte growth factor/scatter factor and MET signalling. Proc Natl Acad Sci USA. 2006 Mar 14;103(11):4046–51.
- 52. How do weknow all this? Gherardi E, Sandin S, Petoukhov MV, Finch J,Youles ME, Ofverstedt L-G, et al. Structural basis of hepatocyte growth factor/scatter factor and MET signalling. Proc Natl Acad Sci USA. 2006 Mar 14;103(11):4046–51.
- 53. How do weknow all this? Gherardi E, Sandin S, Petoukhov MV, Finch J,Youles ME, Ofverstedt L-G, et al. Structural basis of hepatocyte growth factor/scatter factor and MET signalling. Proc Natl Acad Sci USA. 2006 Mar 14;103(11):4046–51.
- 54. How do weknow all this? Gherardi E, Sandin S, Petoukhov MV, Finch J,Youles ME, Ofverstedt L-G, et al. Structural basis of hepatocyte growth factor/scatter factor and MET signalling. Proc Natl Acad Sci USA. 2006 Mar 14;103(11):4046–51.
- 55. Gherardi E, SandinS, Petoukhov MV, Finch J,Youles ME, Ofverstedt L-G, et al. Structural basis of hepatocyte growth factor/scatter factor and MET signalling. Proc Natl Acad Sci USA. 2006 Mar 14;103(11):4046–51. How do we know all this?
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- 64. Chartier M, ChénardT,Barker J, Najmanovich R. Kinome Render: a stand-alone and web-accessible tool to annotate the human protein kinome tree. PeerJ. 2013 Aug 8;1:e126.
- 65. Chartier M, ChénardT,Barker J, Najmanovich R. Kinome Render: a stand-alone and web-accessible tool to annotate the human protein kinome tree. PeerJ. 2013 Aug 8;1:e126.
- 66. Chartier M, ChénardT,Barker J, Najmanovich R. Kinome Render: a stand-alone and web-accessible tool to annotate the human protein kinome tree. PeerJ. 2013 Aug 8;1:e126.
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- 72. EGF PDGF Insulin VEGF FGFROR NGF MuSK Clinically Significant Families
- 73. Gefitinib Erlotinib Lapatinib Cetuximab Neratinib Osimertinib Panitumumab Vandetanib Necitumumab Clinically Significant Families EGFPDGF Insulin VEGF FGF ROR NGF MuSK
- 74. Insulin IGF-1 XMetA 4548-G05 Mecasermin Clinically Significant Families EGFPDGF Insulin VEGF FGF ROR NGF MuSK
- 75. Imatinib Sunitinib Sorafenib Pazopanib Crenolanib Nilotinib Cediranib Clinically Significant Families EGFPDGF Insulin VEGF FGF ROR NGF MuSK
- 76. Sunitinib Sorafenib Pazopanib Cediranib Motesanib Axitinib Linifenib Ponatinib Clinically Significant Families EGFPDGF Insulin VEGF FGF ROR NGF MuSK
- 77. Sorafenib Pazopanib Cediranib Lenvatinib Dovitinib Brivanib Nintedanib Ponatinib Lucitanib Clinically Significant Families EGFPDGF Insulin VEGF FGF ROR NGF MuSK
- 78. PD 90780 Clinically SignificantFamilies EGF PDGF Insulin VEGF FGF ROR NGF MuSK
- 79. Clinically Significant Families EGFPDGF Insulin VEGF FGF ROR NGF MuSK
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- 83. Insulin Receptor:What’s different? TypicalRTK Insulin Receptor
- 84. Insulin Receptor:What’s different? TypicalRTK Insulin Receptor
- 85. Insulin Receptor:What’s different? TypicalRTK Insulin Receptor Monomer Tetramer Dimerizes during activation Already a tetramer Extracellular domain 2 Alpha chains Intracellular domain 2 Beta chains α β β α α β β α HubbardSR.The Insulin Receptor: Both a Prototypical andAtypical ReceptorTyrosine Kinase. Cold Spring Harb Perspect Biol. 2013 Mar 1;5(3):a008946.
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- 87. RTK: Manifest Patterns Retinitispigmentosa Hypogonadotrophic hypogonadism Trigoncephaly Pfeiffer syndrome Osteoglophonic dysplasia Apert syndrome Crouzon syndrome Jackson–Weiss syndrome Achondroplasia Hypochondroplasia LADD syndrome Thanatophoric dysplasia Piebaldism Myasthenic syndrome Congenital insensitivity to pain Robinow syndrome CML GIST Glioma Renal cell carcinoma Endocrine pancreatic cancer Mammary carcinoma Lung cancer Colorectal cancer McDonell LM, Kernohan KD, Boycott KM, Sawyer SL. Receptor tyrosine kinase mutations in developmental syndromes and cancer: two sides of the same coin. Hum Mol Genet. 2015 Oct 15;24(R1):R60–6.
- 88. RTK: Manifest Patterns Retinitispigmentosa Hypogonadotrophic hypogonadism Trigoncephaly Pfeiffer syndrome Osteoglophonic dysplasia Apert syndrome Crouzon syndrome Jackson–Weiss syndrome Achondroplasia Hypochondroplasia LADD syndrome Thanatophoric dysplasia Piebaldism Myasthenic syndrome Congenital insensitivity to pain Robinow syndrome CML GIST Glioma Renal cell carcinoma Endocrine pancreatic cancer Mammary carcinoma Lung cancer Colorectal cancer McDonell LM, Kernohan KD, Boycott KM, Sawyer SL. Receptor tyrosine kinase mutations in developmental syndromes and cancer: two sides of the same coin. Hum Mol Genet. 2015 Oct 15;24(R1):R60–6.
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- 92. Insulin binds to Cell surfacereceptor 1995 2001 Before 1960 1960s 1970 1978 1979 1980-90 Evolution
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- 95. Discovery of various RTKfamilies 1995 2001 2004 2008 2010 Before 1960 1960s 1970 1978 1979 1980-90 Evolution
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- 100. RTK selectivity and SH2domain sites 1995 2001 2004 2008 2010 2011 2016 2018 1970 1978 1979 1980-90 Evolution
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- 102. RTK role otherareas: First: Renal fibrosis 1995 2001 2004 2008 2010 2011 2016 2018 1979 1980-90 Evolution
- 103. ALK family inCancer 1995 2001 2004 2008 2010 2011 2016 2018 1980-90 Evolution
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- 106. Development & Pipeline Preclinicalphase 411
- 107. Development & Pipeline Preclinicalphase Clinical phase 411 164
- 108. 32 Preclinical phase Clinicalphase Market Development & Pipeline 32 411 164
- 109. Development & Pipeline ImatinibCML 2001 Semaxanib Prematurely ended phase III 2003 Lestaurtinib AML - ORPHAN 2006 Nilotinib CML 2007 Vandetanib Medullary thyroid cancer 2011 Sunitinib RCC 2011 Crizotinib NSCLC 2011 Regorafenib Colorectal cancer 2012 Axitinib Ca Breast 2012
- 110. Development & Pipeline AfatinibNSCLC 2013 Erlotinib NSCLC 2014 Gefitinib Imatinib resitant CML 2015 Dasatinib Discontinued 2016 Tivozanib RCC - EMA 2017 Neratinib Ca Breast 2017 Sorafenib AML AWAITE D Lapatinib Ca Breast AWAITE D
- 111. • Whether todevelop at MTD or OBD? • Should genome sequencing be done? • Should we include mutants in the trial? • Binding to a mutated receptor? • Therapeutic resistance Challenges
- 112. Open House Open House OpenHouse Open House