Cancer Drug Design: Proteins (DONE)

Question 1

Why are proteins used as therapeutic targets?

Answer 1

Proteins have a greater structural variety than DNA- potentially more attractive for drug design
Targeting a specific protein may reduce side effects and toxicity by only modifying a particular aspect of the cancer cells biology

Question 2

EGFR inhibitors

Answer 2

EGFR is over expressed or over active in many cancer cells

This results in uncontrolled cellular proliferation and tumour development

Question 3

Design process of Gefitinib

Answer 3

4-Anilinoquinazoline was identified as an important pharmacophore for EGFR tyrosine kinase inhibition
SARs determined
Metabolites isolated and identified as oxidation products
Replace metabolically susceptible groups with atoms of a similar size. F is a good bioisostere of H. Cl is a good bioisostere of Me.
A large number of analogues were synthesized to improve PK and physical properties.

Question 4

Final Gefitinib structure

Answer 4

It was not the most active compound investigated, but achieved moderate and sustained plasma concentrations over 24h.
Clinical trials confirms the molecule had good oral bioavailability, and the plasma half life was suitable for once daily dosing.
Biological activity correlates to EGFR signal transduction pathway inhibition

Question 5

Tarceva- me too

Answer 5

Erlotinib was licensed in the UK and USA for non-small cell lung cancer and pancreatic cancer (2003)
It is also an EGFR inhibitor, containing the 4-anilinoquinazoline pharmacophore, as well as other common features- extended chain, electron donating groups, H bonding group, hydrophobic group
Tarceva is a rival product to Iressa and an example of a me-too drug

Question 6

DNA repair- a new target for cancer therapy

Answer 6

Mammalian cells have developed complex mechanisms to protect their DNA/genome from damage e.g. environmental or xenobiotic
Estimated at least 10,000 DNA damage events per day per cell- cellular respiration, sunshine, cigarette smoke, car exhaust, burnt food
DNA repair stops everyone from dying of cancer by 20

Question 7

Repairing DNA damage

Answer 7

Many enzymes repair DNA damage including PARP and (in breast and ovarian tissue) BRCA1 and BRCA2
BRCA1/2 are tumour suppressors (gene or protein)
Breast cancer families, especially if young occurrence, are often due to faulty BRCA1/2
Women with BRCA gene faults have 50-90% chance of developing breast cancer

Question 8

A new therapeutic target for breast and ovarian cancer

Answer 8

Healthy breast and ovarian cells express BRCA1 and BRCA2
Ovarian and breast cancers are often deficient in BRCA1/2
If PARP is inhibited in these cells, DNA repair is not possible, and the cancerous cell will die > a therapeutic target

Question 9

How does PARP work?

Answer 9

Knowledge of substrate binding helps drug design- suggests a lead compound
PARP uses NAD+ as a substrate
The nicotinamide portion binds to the active site, while the adenine dinucleotide portion forms a protein bound polymer- a cellular signal for DNA repair

Question 10

Restricted conformation produces nanomolar PARP inhibitors

Answer 10

Heterocyclic derivatives are highly active PARP inhibitors by restricting the number of conformations to a single isomer
The benzoxazole differed from the lead by one N atom only. The benzimidazole is a bioisostere of the benzoxazole. A novel chemical structure for PARP inhibition had been identified. The shape of the active site of PARP deduced from the SAR.

Question 11

Active site binding

Answer 11

The 3D protein structure of PARP was obtained after traditional medicinal chemistry drug design
The SAR predicted from the medicinal chemistry was confirmed
Subsequent computer aided drug design has further improved the pharmacophore

Question 12

Olaparib (Lynparza)

Answer 12

Researchers used a novel benzamide mimic and modified the phenyl ring with a large number of chemically diverse derivatives from a library to find the best fit
Licensed Dec 2014 for advanced ovarian cancer with BRCA mutations
Ovarian cancer is a silent killer- olaparib is an important new drug and first in class
Clinical trials of PARP inhibitors for breast cancer are currently ongoing

Question 13

Conclusions

Answer 13

Proteins are attractive target in cancer therapy, a wide range of cancer specific processes can be targeted
Selectivity vs normal tissue is still as issue, but not targeting the DNA reduces the possibility of mutations
The most biologically active molecule is not always the best drug candidate as other factors must be taken into consideration
Universities can compete with big pharma