L4: Cancer Drug Discovery

Question 1

What are the sources of new drugs?

Answer 1

• From traditional remedies (paclitaxel)
• Biological therapeutics (vaccines, antibodies, RNA)
• Serendipitous discovery (screening natural or synthetic chemical libraries for things that change the phenotype)
• Structure-based design (computational chemistry)

Question 2

What are the examples of traditional remedies?

Answer 2

• Paclitaxel example
  o Pacific yew tree
  o Chemotherapy for breast and ovarian cancers
  o Taxanes are a class of several microtubule disrupting drugs
• Penicillin antibiotics
• Rapamycin
  o Used to treat many types of cancers
  o Inhibits signalling in the cell

Question 3

What is the drug project operating model?

Answer 3

• Preclinical
  o Target selection: protein activity implicated in disease
  o Hit ID: screen compounds for a potential drug
  o Lead ID: a prioritized or optimized hit displaying high potency or selectivity
  o Candidate drug: usually one or two candidates will be tested across a suite of biological assays (in vitro and in vivo)
• Clinical
  o Phase I: initial human testing (safe dose and pharmacokinetics established)
  o Phase II: effectiveness in patients and more safety testing
  o Phase III: randomized multicentre trials on randomized patient groups (300-1000)
  o Launch: regulatory approval

Question 4

What happens genetically in BCR-ABL leukemia?

Answer 4

o In this disease you develop chromosomal translocation – develop Philadelphia chromosome, proportion of chromosome 9 translocates to chromosome 22
o Consequence of translocation: gene ABL (tyrosine kinase) gets translocated to protein called BCR, which makes a gene fusion, leading to dysregulation of kinase activity

Question 5

What’s the drug used to treat BCR-ABL leukemia?

Answer 5

Glivec