Receptor Tyrosine Kinase

1. Dr. Saurabh Patil JR-1 Guided by: 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 years old male • Routine employee check-up • No complaints • Incidental splenomegaly Your patient

4. Your patient RT PCR for BCR ABL mRNA 70% Blasts 10%

5. Your patient RT PCR for BCR ABL mRNA 70%

6. Your patient

7. Chronic Myeloid Leukemia Your patient

9. Receptors

10. Receptors Neuroscience. 2nd edition. Purves D,Augustine GJ, Fitzpatrick D, et al., editors. Sunderland (MA): Sinauer Associates; 2001.

14. Receptors

15. Receptors

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

18. ReceptorTyrosine Kinase

20. ReceptorTyrosine Kinase KINASE P P P A P P A Target Target

22. ReceptorTyrosine Kinase KINASE P P P A P P A Ty r Ty r Ty r

24. ReceptorTyrosine Kinase Tyrosine Kinases Receptor Non-Receptor

26. Structure

27. Structure DYNAMIC

28. Structure MONOMER

29. Structure MONOMER DI

30. Structure http://www.mun.ca/biology/desmid/brian/BIOL2060/BIOL2060-14/14_16.jpg

31. Structure

32. Structure

33. Structure

34. Structure

35. Structure

36. Structure

37. Activation

38. Activation TETHERED STATE TeramuraY, Ichinose J,Takagi H, 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,Takagi H, 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,Takagi H, 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,Takagi H, 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,Takagi H, 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,Takagi H, 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. Receptor tyrosine 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. Receptor tyrosine kinases: mechanisms of activation and signaling. Curr Opin Cell Biol. 2007 Apr;19(2):117–23.

47. How do we know all this?

48. How do we know 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, 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. How do we know all this?

56. Signaling Pathways

58. Signaling Pathways !

63. Families of RTK

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.

67. Families of RTK

68. Families

69. Families Clinically significant

70. Clinically Significant Families

71. Clinically Significant Families

72. EGF PDGF Insulin VEGF FGF ROR NGF MuSK Clinically Significant Families

73. Gefitinib Erlotinib Lapatinib Cetuximab Neratinib Osimertinib Panitumumab Vandetanib Necitumumab Clinically Significant Families EGF PDGF Insulin VEGF FGF ROR NGF MuSK

74. Insulin IGF-1 XMetA 4548-G05 Mecasermin Clinically Significant Families EGF PDGF Insulin VEGF FGF ROR NGF MuSK

75. Imatinib Sunitinib Sorafenib Pazopanib Crenolanib Nilotinib Cediranib Clinically Significant Families EGF PDGF Insulin VEGF FGF ROR NGF MuSK

76. Sunitinib Sorafenib Pazopanib Cediranib Motesanib Axitinib Linifenib Ponatinib Clinically Significant Families EGF PDGF Insulin VEGF FGF ROR NGF MuSK

77. Sorafenib Pazopanib Cediranib Lenvatinib Dovitinib Brivanib Nintedanib Ponatinib Lucitanib Clinically Significant Families EGF PDGF Insulin VEGF FGF ROR NGF MuSK

78. PD 90780 Clinically Significant Families EGF PDGF Insulin VEGF FGF ROR NGF MuSK

79. Clinically Significant Families EGF PDGF Insulin VEGF FGF ROR NGF MuSK

80. Insulin Receptor:What’s different?

81. Insulin Receptor:What’s different? Typical RTK

82. Insulin Receptor:What’s different? Typical RTK

83. Insulin Receptor:What’s different? Typical RTK Insulin Receptor

84. Insulin Receptor:What’s different? Typical RTK Insulin Receptor

85. Insulin Receptor:What’s different? Typical RTK 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.

86. RTK: Manifest Patterns

87. RTK: Manifest Patterns Retinitis pigmentosa 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 Retinitis pigmentosa 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.

89. Evolution

90. Understanding Protein Kinases Before 1960 1960s 1970 1978 1979 1980-90 Evolution

91. Discovering EGF, NGF 1995 Before 1960 1960s 1970 1978 1979 1980-90 Evolution

92. Insulin binds to Cell surface receptor 1995 2001 Before 1960 1960s 1970 1978 1979 1980-90 Evolution

93. Discovered FGF 1995 2001 2004 Before 1960 1960s 1970 1978 1979 1980-90 Evolution

94. Discovered PDGF 1995 2001 2004 2008 Before 1960 1960s 1970 1978 1979 1980-90 Evolution

95. Discovery of various RTK families 1995 2001 2004 2008 2010 Before 1960 1960s 1970 1978 1979 1980-90 Evolution

96. PI3KAkt signaling pathway established 1995 2001 2004 2008 2010 2011 Before 1960 1960s 1970 1978 1979 1980-90 Evolution

97. Imatinib “Gleevec” FDA Approval 1995 2001 2004 2008 2010 2011 2016 Before 1960 1960s 1970 1978 1979 1980-90 Evolution

98. Mutations and resistance, Gefitinib 1995 2001 2004 2008 2010 2011 2016 2018 Before 1960 1960s 1970 1978 1979 1980-90 Evolution

99. “Binding heterogeneity” for EGFR 1995 2001 2004 2008 2010 2011 2016 2018 1960s 1970 1978 1979 1980-90 Evolution

100. RTK selectivity and SH2 domain sites 1995 2001 2004 2008 2010 2011 2016 2018 1970 1978 1979 1980-90 Evolution

101. FGFR inhibitor resistance 1995 2001 2004 2008 2010 2011 2016 2018 1978 1979 1980-90 Evolution

102. RTK role other areas: First: Renal fibrosis 1995 2001 2004 2008 2010 2011 2016 2018 1979 1980-90 Evolution

103. ALK family in Cancer 1995 2001 2004 2008 2010 2011 2016 2018 1980-90 Evolution

104. Development & Pipeline

105. Development & Pipeline PIPELINE

106. Development & Pipeline Preclinical phase 411

107. Development & Pipeline Preclinical phase Clinical phase 411 164

108. 32 Preclinical phase Clinical phase Market Development & Pipeline 32 411 164

109. Development & Pipeline Imatinib CML 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 Afatinib NSCLC 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 to develop 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 Open House Open House

Receptor Tyrosine Kinase

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