Drug Targets - Mathias Flashcards
The “magic bullet theory”
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
How do autologous and allogenic vaccines work?
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
What is a paratope?
The region of the antibody that binds the epitope
How are antibodies used in pharmaceutical practice?
- 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
Fusion proteins
produced by recombinant DNA
Emerging themes in drug development
- biologic agents
- therapeutic antibodies (mAbs)
- vaccines vs endogenous targets
- gene therapy
- adenoviral gene delivery
- RNA interference, antisense therapy, siRNA
- allogenic/autologous stem cell treatment
compound centric drug development - rationale + testing procedure
- secondary or unwanted side effects observed in animal models or clinic
- library of chemical analogs is further tested in animal models to optimise SAR
Etanercept
A fusion protein
TNF receptor is fused to the Fc portion of IgG1
Acts as a soluble TNF inhibitor “decoy receptor”
Latanoprost
- 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
target-centri drug development rationale + example
- rationale: genetic findings and molecular biology
- Example: imatinib
- commonly used in cancer treatment
Imatinib (Gleevec)
- 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
Two types of cancer vaccines and examples
- preventive
- HPV: Gardasil, Cervarix
- treatment vaccines
- customised to each patient (Sipuleucel-T)
- synthetic antigens similar to cancer proteins
- autologous vaccines
- allogenic vaccines
Examples for recetpor type tyrosine kinases
- insulin R
- IGF type I R
- EGFR
- VEGFR
- PDGFR
Why are protein kinases so important in cancer therapy?
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”
What do protein kinases mediate?
mediate growth, proliferation, and differentiation
