Drug Targets - Mathias

Question 1

The “magic bullet theory”

Answer 1

The idea that if you only interact with one protein you are going to get the desired effect and you will get no ADEs

–> definitely not the case for protein kinases; most, if not all, interact with several other targets, due to their very conserved ATP-binding site

latest approach: build allosteric inhibitors

Question 1

How do autologous and allogenic vaccines work?

Answer 1

Take cells and de-vitalise them (by radiation). Then give them to the patient and try to induce an immune response against fragments of these

Question 2

What is a paratope?

Answer 2

The region of the antibody that binds the epitope

Question 2

How are antibodies used in pharmaceutical practice?

Answer 2

• immunoglobulins
  
  • boosters for immunocomprimised patients, e.g. AIDS, cancer
• monoclonal antibodies
  
  • primes specific targets for elimination by the immune system
• fusion proteins
  
  • non-immunogenic, sequester ligands

Question 3

Fusion proteins

Answer 3

produced by recombinant DNA

Question 4

Emerging themes in drug development

Answer 4

• biologic agents
  
  • therapeutic antibodies (mAbs)
• vaccines vs endogenous targets
• gene therapy
  
  • adenoviral gene delivery
  • RNA interference, antisense therapy, siRNA
  • allogenic/autologous stem cell treatment

Question 5

compound centric drug development - rationale + testing procedure

Answer 5

• secondary or unwanted side effects observed in animal models or clinic
• library of chemical analogs is further tested in animal models to optimise SAR

Question 6

Etanercept

Answer 6

A fusion protein

TNF receptor is fused to the Fc portion of IgG1

Acts as a soluble TNF inhibitor “decoy receptor”

Question 8

Latanoprost

Answer 8

• prostaglandin analouge (PGF2alpha)
• compound-centric approach
• lowers intraocular pressure, used in glaucoma treatment
• during development, they tried to find IOP reducing effect without inflammatory effects
• different animal models to assess different effects
• one of the essential medicines

Question 9

target-centri drug development rationale + example

Answer 9

• rationale: genetic findings and molecular biology
• Example: imatinib
• commonly used in cancer treatment

Question 9

Imatinib (Gleevec)

Answer 9

• inhibits the protein kinase BCR-ABL; first in line treatment
• first-in-class oral antineoplastic protein kinase inhibitor
• in CML; philadelphia chromosome t(9;22)
• target-centric approach
• Inhibitors were screened in vitro
  
  • PoC in enzyme activity assays and ABL-expressing cell cultures
  • transgenic animal models preceeded clinical trials
• orphan drug –> FDA fast track

Question 10

Two types of cancer vaccines and examples

Answer 10

• preventive
  
  • HPV: Gardasil, Cervarix
• treatment vaccines
  
  • customised to each patient (Sipuleucel-T)
  • synthetic antigens similar to cancer proteins
  • autologous vaccines
  • allogenic vaccines

Question 11

Examples for recetpor type tyrosine kinases

Answer 11

• insulin R
• IGF type I R
• EGFR
• VEGFR
• PDGFR

Question 12

Why are protein kinases so important in cancer therapy?

Answer 12

Because they are involved in important hallmark pathways

Examples:

• EGFR inhibitors target “sustaining proliferative signal”
• Cyclin-dependent kinase inhibitors target “evading growth suppressors”
• Inhibitors of HGF/c-Meth target “activating invasion & metastasis”
• Inhibitors of VEGF signaling target “inducing angiogesis”

Question 13

What do protein kinases mediate?

Answer 13

mediate growth, proliferation, and differentiation

Question 14

Targets of endogenous vaccines

Answer 14

• cancer vaccines
  
  • immunise against tumourspecific antigens
• hypercholesterolemia (CETP)
• Hypertension (AGT: targets RAS)
• diabetes (reduce immune response against beta cells)

Question 15

What is the most intensely studied protein class in clinical trials?

Answer 15

Protein kinases

Question 16

Diseases where Ritixumab is used

Answer 16

• lymphoma, leukemia
• autoimmune disorders (e.g. RA), immunomodulatory
• transplant recejction, immunosuppressive

Question 18

What is a drug target?

Answer 18

“A biological moiety with which a pharmacological agent interacts, thereby inducing a therapeutic effect”

Question 19

What is an epitope?

Answer 19

The region of the antigen recognised by an antibody

Question 20

Procedure of target-centric drug development

Answer 20

• In vitro experiments preceed animal data
• optimisation in vitro - use of cell lines and you validate in vitro long before you go into animals

Question 22

Insulin signaling pathway acts on

Answer 22

• fatty acid biosynthesis
• glycolysis/gluconeogenesis
• metabolism
• apoptosis

Question 23

Rituximab - mechanism of action

Answer 23

1. binds CD20
2. activates the complement system
3. engages with NK cells
4. engages with macrophages

Question 24

Compound-centric drug development + example drug

Answer 24

“optimise the drug based on SAR in order to get rid of side effects”

iterative optimization process

Example: Latanoprost