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Molecular Targets: Definition and classification - Coggle Diagram
Molecular Targets: Definition and classification
Open Targets
platform
An initiative to generate evidence on the
validity of therapeutic targets
based on
genome-scale experiments
and
analysis
Helps
identifying
and
prioritizing
targets associated with a disease, so that they can be further investaigated
Information on both:
Targets associated with a disease
Diseases associated with a target
Provides information on:
Biological validity
(= how likely it is that the target contributes causally to the disease)
Biological impact assessment
(= how modulating such target could provide benefit)
Properties of a target include
druggability
Druggability = property of a biological molecule to be
modulated by a drug
The drug must be
selective for the target
Usually, biological targets are proteins, but they can be
any biological molecule
Currently available drugs only cover a fraction of druggable targets
Of all human genes, about 5000 are druggable. However, only 600 of them are targeted by drugs
Efforts are being made to shed light on the druggable genome, to discover innovative targets
IDG
(
Illuminating Druggable Genome
)
Program
Drugs evolution:
Biologics
: therapeutic peptides, recombinant proteins, therapeutic Ab
Target classes
: targets expressed on cell surface/transmembrane/extracellular space
P&C
: high specificity, complex delivery, complex manufacturing reproducibility, extracellular targets
Next generation therapeutics
based on genomics: RNA-based therapies, cell therapy, gene editing
Small molecules
: natural compounds, synthetic analogs, new chemical entities
Target classes
: receptors, enzymes, transporters, channels, TFs, nucleic acids
P&C
: very diffused and common, easy delivery, low specificity
Main target classes
Transporters
Receptors
GPCRs
Easily druggable by targeting the
ligand binding site/allosteric site
. Targeted by
40% of available drugs
Intracellular receptors
Ligand gated ion channels
Enzymes
Easily druggable by designing
agents similar to endogenous ligands
Databases of drug/target interactions
IUPHAR
Curated database of drugs and relative targets
Drug-centered databases
Therapeutic Target Database
DrugBank
DrugCentral
ChEMBL
Target-centered databases
Pharos
Targets are classified based on the existing knowledge (clinical, chemical, biological, dark)
Druggable genome database
Target Central Resource Database
Both resources developed by IDG program
Insights into target classes
Biologics
Protein therapeutics
Advantages
compared to SMOL
High
specificity
, reducing adverse effects
They hold
complex functions
that SMOL cannot mimic
Usually
well tolerated/no IS reaction
as they are human proteins
Useful for diseases in which
target is deleted/mutated
5.
Faster FDA approval
Room for different
patenting
based on form and function
Different
classes
based on mechanism of activity
Enzymatic/regulatory activity
Special targeting activity
Protein vaccines
Diagnostic agents
Disadvantages
and
challenges
Complex production
PK
can be disadvantageous (administration, solubility, stability)
They require
PTMs
to be active
Can elicit
IS response
Costly
Next generation therapeutics
RNA therapeutics
Different agents available to modify gene expression
Increase gene expression
Small molecules, miRNA mimics, miRNA expression vectors, sineUP
Decrease gene expression
ASOs, LNA, siRNAs, antagomirs, miR sponges, SMIRs
Examples:
Spinraza
for the treatment of SMA with ASOs targeting SMN2 splicing site (IV administration);
Risdiplam
with the same mechanims, but oral administration
FDA approval iter
2 different FDA centers regulate SMOL and biologics/new therapies, and the approval pathways are different
Center for Drug Evaluation & Research (
CDER
)
Center for Biologics Evaluation & Research (
CBER
)
Different areas of application:
Biologics mostly approved for cancer therapy, few to target the NS
Currently, the % of biologics and SMOL approved is about the same