WEEK 4 - Medicinal chemistry - Molecular targeted drug design and development Flashcards
(18 cards)
What is the most commonly mutated gene in cancer
P53
- Responsible for checking genome during cell cycle
- Loss of P53 = loss of control = cells can mutate + mutations aren’t spotted
- Humans only have 2 copies of P53
= don’t require many mutations to loose compelte function- other mammals have more copies = even if 1 mutates still have others to detect mutations
List Genetically Targeted Agents
- BRAF Inhibtor
- KRAS Inhibitor
- Inhibition of cell to produce KRAS
- siRNA - stops mRNA from making protein
- CRISPRa - edits protein out of genome
BRAF Inhibitor
cancer used freq. in, example,
BRAF gene mutated in some cancers
- Had good efficacy but wasn’t sustained
- Good response in cancer after 2 weeks use but by 6 months of use cancer returned + grown
- Used freq. in melanoma (V600E mutation test, if have mutation = eligibile)
- e.g. Vemurafenib
KRAS G12C Inhibitor
Info, MoA, Example
KRAS = highly mutated protein in many cancer
- an upstream mediator of MEK-RAF pathway
- a mediator for cancer signalling processes ~ surival, proliferation, differntiation
- Exchanges GTP
-E.g. KRAS G12C inhibitor
- glycine 12 is mutated to cysteine
MoA
- Forms covalnet bond with cystenine = irreversible inhibitor
- Selective to KRAS G12C (mutated KRAS ONLY seen in cancer cells)
NOTE: Discovery of successful inhibitor took many decades
- improevment still needed
- after 2 years mant pts progress / die = limited benefits
List the key challenges with developing genetically targeted anti-cancer therapies
a.k.a. molecularly targeted therapies
- Introduce selection pressures = resistance develops
- cancer cell find resitant pathways
- resistant cells = survive
- Resistance = multiple drugs have to be developed which target emerging resistances
- emerging during clincal trials
- emerged due to selection pressure
What 3 ways can resistance to genetically targeted agents develop
- Induction of efflux pumps
- pumps drug out - Mutations in target protein
- e.g. ↑ mutation = drug ineffective
- Signalling changes
- i.e. signalling pathway drug is invovled in is bypassed
- e.g. BRAF signalling bypassed = cell can survive without BRAF therefore inhibiton of BRAF has no effect
What impact does these challenges have on the need for multiple generations of drugs
Multiple drugs have to be developed which target emerging resistances
- emerging during clincal trials
- emerged due to selection pressure
- Found improved efficacy in giving 2nd gen drug before 1st gen drug
- WHY: the harder + earlier hit tumour = ↓ time to mutate + find resistance pathway
What are the issues with Immune Checkpoint inhibitors e.g. PD-L! inhibitor
Immunotherapy
- Has low repsonse rate
- unaware which pts will respond before treatment intitation
- Poor understanding of the genetic drivers for sensitivity to immunotherapy
- not sure what to look for in pts
Targeting ubiquitin proteasome system
How body degrades unwanted / denatured proteins
(protein degradation)
- E1 ligase binds to ubiquitin
- Ubiquitin is transferred to an E2 ligase
- E2-ubiquitin complex binds to E3 ligase
- E3 recognises protein it wants to get rid off + trasnfers ubiquitin to this protein
- Polyubiquitination occurs (chain of ubiquitins attached to protein)
- Ubiquitin chain acts as flag to proteasome system
- System takes ubiquitin + degrades protein
What is the MoA of PROTACs
How body degrades unwanted / denatured proteins
PROTACs - small molecule drugs joined by a linker
- STRCUTURE: Poi ligand ~ linker ~ E3 ligand
PROTAC MoA:
1. Poi ligand binds to protein we want to denature (POI)
2. E3 ligand binds to E3 (joined to E2-ubiquitin complex)
3. PROTAC brings protien into close proximity with E3 ligase
4. Allows E3 to transfer ubiquitin to protein
5. Polyubiquitinisation
6. Protein degradation by proteosome system
7. PROTAC then finds another protein
NOTE: PROTACs - PROteolysis TArgeting Chimeras
What are the advantages of PROTACs
ADVANTAGES:
- Undamaged during process, moves to enxt protein
- Can target proteins that have resistant mutations in specifc location
- Can target undruggable proteins (i.e. unfunctional site)
- Enables complete removal of protein
- Have potential to use them at much lower doses / conc.
- normal inhibitors require saturation of site
- PROTACS destroy the protein = doesnt need to high level binding
- Potential for selectivity
What are the disadvantages of PROTACs
DISADVANTAGES:
- Small molecules BUT have large MW = ↓ permeability and solubility
- Potential for loss of selectivity
- if molecule has low level off target binding that causes efficient ubiquitin transfer = degrade wrong protein
- Potential off-target effects
What are the advantages and disadvantages of ADCs
ADCs - antibody drug conjugates
ADV:
- Selective for tumour cell = limit toxicity
- limit off-target effects for drugs used in chemo (is tumour specific)
- improve maximum tolerated dose
= kill more cancer cells + ↓ pt SE
- improves pt efficacy
- e.g. in tumour unresponsive to chemo
DISADV:
- Potential lack of specificity (due to target receptor expression else where)
- Long half life = in circulation for long
- may have undesired payload released = toxic
- Penetration into tumour = effciacy limited
What is the MoA for Degrader Antibody Conjugates
PROTACs conjugated to ADCs via cleavable linker
- ADC binds to antigen on cell surface + complex is internalised
- PROTAC is cleaved from ADC + released from endosome
- PROTAC forms complex between POI and E3 ligase
- E3 transfers ubiquitin from E2
- Polyubiquitinisation
- Degradation by proteosome system
What are the advantages and disadvantages of Degrader Antibody Conjugates
ADV:
- Targeted therapy to specific cells based on the antigen / receptor expression
DIS:
- Expensive
- Complex medicine
MoA of Peptide Drug Conjugates
spc. CCL2
Proteins with cytotoxic payload attached
- e.g. attach cytotoxin to CCL2
MoA:
1. Immune cells express high levels of CCR2
2. CCR2 responds to signals produced by CCL2 protein
3. Causes monocytes / macrophages to migrate towards site + internalise protein
4. Drug is released into monocyte
NOTE:
- If cell does not express CCR2 = no uptake of CCL2 = no effect
What are the advantages and disadvantages of Peptide Drug Conjugates
ADV:
DISADV:
- Lack of specificity
- Insuffcient activity against earlier disease
- Only useful in cells rapidly dividing
- CMML cells were slow dividing
Advantages of NAMPT inhibitors
AIM: combat issue of CMML cells being slow dividing cells
- payload atatched only kills rapidly dividing cells
ADV:
- High potency
- Broad structure-activity relationship
- Directly induces apoptosis (independent of cell cycle)
- depeletes NAD
