Lesson 9 Bcl-2, ABT-737, Navitoclax

• CRICOS Provider 00115M
• MED3ATA Cancer Module

  
• Christine Hawkins
• Lecture 9.1: Resisting Cell Death
• Hallmark Bcl‐2
• Commonwealth of Australia
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• Brown text is examinable, grey text is just for your interest: not examinable
• Throughout these cancer lectures: Brown text is examinable, Grey text is just for your interest: not examinable
• Targeting Bcl-2


  Many companies screen for lead compounds that bind and affect the activity of molecules implicated in particular cancers
• Developing drugs targeting Bcl-2 and relatives


  1. Structure-based design

  2. Screening for lead compounds that bind and affect activity

  3. Any protein that promotes or inhibits oncogenesis can be a target
• Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646‐74.

  
• ABT-737


  • Low molecular weight compounds screened for molecules that bound to critical groove of Bcl-xL: "lead compounds"
  • Structures of Bcl-xL/compound complexes analysed and variants screened to optimise binding
  • More screening to find compounds that bound elsewhere within the groove, these compounds optimised
  • Chemical links made between molecules occupying distinct sites
  • Chemical tinkering improved specificity of binding
• ABT-737

  • Binds strongly to Bcl-xL and Bcl-2
  • Does not significantly interact with other Bcl-2 relatives eg Mcl-1
• Hallmark 4: resisting cell death

  • Apoptosis signalling
  • Oncogenic activity of Bcl‐2
  • Targeting Bcl‐2
  • ABT‐737, Navitoclax, Venetoclax
  • Tumour suppressor p53

  
• ABT-737 binds to Bcl-xL and Bcl-2


  Expected to kill cancer cells whose survival depends on Bcl-xL and/or Bcl-2 (but not eg Mcl-1)
• Apoptosis removes dangerous cells: cancerous, autoimmune specificities, infected

  
• ABT-737 activity in vivo in lung cancer xenograft model

  • Provoked complete regression of 77% of tumours
• Insufficient apoptosis can contribute to cancer development and resistance to anti‐cancer treatment
• Navitoclax (ABT-263)


  Orally bioavailable compound, similar specificity to ABT-737
• Normal apoptosis in the human adult accounts for over 1011 cell deaths per day (100g)
• Cancer development provokes apoptotic signalling

  
• Navitoclax (ABT-263)


  • Effective in Phase I clinical trials for relapsed or refractory chronic lymphocytic leukaemia (CLL)
  • Dose-limiting toxicity: platelet deficiencies due to inhibition of Bcl-xL activity, which is required for platelet survival
• Defects in apoptotic pathways allows cancers to arise, persist and metastasise
• Drugs that overcome these pathway blocks can be used to treat cancers
• Genomic instability: DNA damage, mutated genes, chromosome mis‐segregation

  
• Before angiogenesis: Lack of nutrients, Immune attack
• During metastasis: Lack of growth factors
• Apoptosis, cancer nipped in the bud

  
• HeLa cells: GFP targeted to the Golgi apparatus (yellow); microtubules (red); nuclei (blue)
• Intrinsic Apoptotic Signalling
• Bcl‐2 gene is translocated in follicular lymphoma

  
• Bcl‐2 translocation in follicular lymphoma

  1. Translocation results in abnormal constitutive (constant) high level Bcl‐2 expression in B cells

  2. Bcl‐2 is also over‐expressed (other mechanisms) in CLL and some other cancers

  
• Lymph node from follicular lymphoma patient

  • Bcl‐2 immunohistochemistry
  • H&E staining of lymph node
• Bcl‐2 promotes cell survival and cancer development

  
• Follicular lymphoma starts slow but becomes aggressive ("transforms") in 45% of cases

  
• Upregulation of Bcl‐2 (e.g. translocation)

  Bcl‐2 promotes cell survival and cancer development