PRINCIPLES OF EARLY DRUG DISCOVERY Flashcards
INFLUENCE OF MAJOR ADVANCEMENTS IN TECHNOLOGY ON DRUG DISCOVERY
NOT A VERY STRONG INFLUENCE, ATTRITION REMAINS VERY HIGH AND THE NUMBER OF NEW SMALL MOLECULE DRUG APPROVALS REMAINS REMARKABLY CONSTANT (FOR THE PAST COUPLE OF DECADES)
- ADVANCES HAVE NOT SIGNIFICANTLY IMPROVED EFFICACY OR PRODUCTIVITY
WHY IS THE NUMBER OF NEWLY APPROVED SMALL MOLECULE DRUGS CONSTANT DESPITE TECHNOLOGICAL AND BIOLOGICAL ADVANCEMENTS?
- NEW DRUG CANDIDATES MUST RESPRESENT A SIGNIFICANT ADVANTAGE OVER STANDARD OF CARE (SOC)
- THERE IS NO MORE ‘LOW HANGING FRUIT’
- DISEASES WITH HIGH UNMENT CLINICAL NEED ARE OFTEN COMPLEX AND HETEROGENOUS, MAY TAKE MANY YEARS TO DEVELOP AND PRESENT LAT
- DISEASE MODELS FAIL TO REFLECT COMPLEXITY OF HUMAN DISEASE (MODELS OFTEN ‘ACUTE’)
- OFTEN POOR TRANSLATION FROM DISEASE MODEL TO CLINICAL CONCEPTS
CONSIDERATIONS WHEN ADDRESSING THE PROBLEM OF STATIC DRUG DISCOVERY?
- DISTINGUISH BETWEEN TOOL MOLECULES AND ACTUAL DRUG CANDIDATES THAT ARE ‘DEVELOPABLE’
- ‘CURE’ VS DISEASE CONTROL (IS CHANGING POOR SURVIVAL RATES TO CHRONIC DISEASE SUFFICIENT)
- QOL AND PATIENT COMPLIANCE
- ISSUES WITH A ‘REDUCTIONIST’ APPROACH - CAN A COMPLEX DISEASE BE MODELLED AS A SINGLE ‘BIOCHEMICAL’ STEP?
- LACK OF EFFECTIVE BIOMARKER RESEARCH
HOW LONG IS THE DRUG DISCOVERY PROCESS USUALLY AND HOW MUCH DOES IT COST?
12-15 YEARS LONG
COSTS > 1 BILLION
ATTRITION RATES IN DRUG DISCOVERY
VERY HIGH!!!
80-90% FAILURE IN EARLY RESEARCH/PRECLINICAL
80/90% FAIL IN CLINIC
LATE FAILURE = VERY EXPENSIVE, AIM TO ‘FAIL EARLY AND CHEAP’!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!
HOW MANY FAILED RCTs HAVE THERE BEEN FOR SEPSIS DRUGS?
ALMOST 100
CONSIDERATIONS/PRINCIPLES OF PICKING A TARGET FOR DRUG DISCOVERY
WHAT DISEASE?
- HIGH UNMET CLINICAL NEED
- COMPETITION?
- PERCEIVED ADVNTAGE OVER STANDARD OF CARE?
DO YOU HAVE A ‘COMPETITIVE’ ADVANTAGE?
- UNDERSTANDING OF DISEASE BIOLOGY THAT IS NOT IN PUBLIC DOMAIN
- ACCESS TO PRORIETARY REAGENTS, ASSAYS, STRUCTURAL DATA?
DO YOU UNDERSTAND WHY PREVIOUS APPROACHES HAVE FAILED?
- LACK OF EFFICACY OR TOLERANCE
- TOXICITIES/SIDE EFFECTS, PATIENT COMPLIANCE?
WHAT SHOULD BE A STARTING POINT OF DRUG DISCOVERY?
A DISEASE-RELEVANT TARGET!!!! (THEN DEVELOP APPROPRIATE ASSAYS, CELLS TYPES, MODELS ETC)
DO NOT START A PROJECT JUST TO GENERATE A VERY POTENT MOLECULES AGAINST PARTICULAR PROTEINS OR PATHWAYS AND THEN GO ‘FISHING’ FOR A CONDITION IT MIGHT BE RELEVANT FOR, DEFINE THE DISEASE FIRST!
+ CONSIDER COMPETITION BEFORE STARTING AND DURING ALL PROJECT PHASES!
WHAT DOES DEFINING ‘RESEARCH TARGET PROFILE’ INCLUDE IN DRUG DISCOVERY?
- MEANS DEFINING WHAT SUCCESS LOOKS LIKE
DOSE, FREQUENCY AND ROUTE?
MINIMUM EFFICACY, SELECTIVITY AND TOXICITY CRITEIA THAT MUST BE MET?
PERCEIVED ADVANTAGE OVER COMPETITION IN THE CLINICAL AND IN DEVELOPMENT?
STAGES OF DRUG DISCOVERY
TARGET ID
TARGET VALIDATION
HIT GENERATION/HTS (100 000 - 1 000 000 COMPOUNDS)
HIT TO LEAD (100s COMPOUND, IDEALLY SEVERAL SCAFFOLDS/SERIES)
LEAD OPTIMISATION (1-2 SERIES)
CANDIDATE (1-2, IDEALLY PROJECT SHOULD GENERATE A BACKUP)
DRUG DISCOVERY IS A ‘FUNNEL’!!!!!!!!!!! –> REQUIRES DECISIONS ON PRIORITIES
WHAT IS ‘PATENT BUSTING’ IN EARLY DRUG DISCOVERY?
FURTHER OPTIMISATION OF KNOWN COMPOUNDS FROM THE LITERATURE OR COMPETITORS, TO MAKE THEM ‘DIFFERENT ENOUGH AND BE ABLE TO CALL THEM YOUR OWN
- THIS IS A STARTING POINT OF ‘GENERATING HITS’ IN EARLY DRUG DISCOVERY
SCREEENING OPTIONS FOR GENERATING ‘HITS’ IN EARLY DRUG DISOVERY
- HIGH THROUGHPUT
- FOCUSED SCREEN (E.G. COMPUNDS KNOWN TO HIT SPECIFIC CLASSES OF TARGETS)
- FRAGMENT SCREEN (SOAKING SMALL, LOW mM ACTIVITY COMPOUNDS INTO CRYSTALS)
- VIRTUAL SCREEN (DOCKING MOLECULES INTO X-RAY STRUCTURE OF PROTEIN TARGET)
- NMR SCREEN (SCREENING FRAGMENTS USING NMR AS A STRUCTURE DETERMINING TOOL)
DESCRIBE THE LEAD OPTIMISATION IN EARLY DRUG DISCOVERY
ASSESSMENT OF POTENTIAL LIABILITIES: OFF TARGET PROFILE (PROMISCUITY), hERG, FORMULATION/CMC ISSUES
ROUTE OF ADMINISTRATION
TARGET LOCATION: INTRACELLULAR, EXTRACELLULAR, MITOCHONDRIAL ETC, TISUE DISTRIBUTION OF TARGET, IS CNS EXPOSURE REQUIRED OR TO BE AVOIDED?
EARLY ADME (4 PHASES OF PHARMACOKINETICS, PK); IN VITRO AND IN VIVO
EFFICACY IN RELEVANT DISEASE MODEL AT ‘WELL TOLERATED’ DOSES
WHAT PREVENTS A ‘TOOL MOLECULE’ FROM BECOMING A ‘CANDIDATE’ IN EARLY DRUG DISCOVERY?
- INSUFFICIENT POTENCY/ACTIVITY TO TRANSLATE (RAPID TOLERANCE OR RESISTANCE DEVELOPS, POOR PHARMACOKINETICS OR PHARMACODYNAMICS..)
- NARROW TI (THERAPEUTIC INDEX) OR MAJOR CONCERNS OVER TOXICITY (ACUTE OR CHRONIC) –> IS TOXICITY ‘ON TARGET’ OR ‘OFF TARGET’?
- POOR ‘DRUG-LIKE’ PROPERTIES (E.G. MOLECULAR WEIGHT, FORMULATION CONCERNS, STABILITY…)
- POTENTIAL FOR DRUG-DRUG INTERACTIONS (DDI)
NOAEL IN DRUG DISCOVERY STANDS FOR:
The no-observed-adverse-effect-level (NOAEL) is an important part of the non-clinical risk assessment.
The no-observed-adverse-effect level denotes the level of exposure of an organism, found by experiment or observation, at which there is no biologically or statistically significant increase in the frequency or severity of any adverse effects of the tested protocol.
WHY DO DRUG DISCOVERY PROJECTS FAIL?
INADEQUATE DRUG LIKE PROPERIES
- TOXICITY
- DRUG-DRUG INTERACTIONS (DDI)
- ADME/PK (PHARMACOKINETICS, 4 PHASES)
- CMC (Chemistry, manufacturing and controls)….
TARGET HYPOTHESIS DID NOT REFLECT CLINICAL REALITY
LACK OF EFFICACY
POORLY PREDICTIV TRANSLATIONAL MODELS
LACK OF COHERENT BIOMARKER STRATEGY
RAPID INDUCTION OF DRUG RESISTANCE
TYPE OF ADMINISTRATION REQUIRED
PATIENTS CARE ABOUT QOL, NOT INNOVATION, METHOD OF ACTION ETC
HOW CAN AI IMPACT DRUG DISCOVERY?
- DRUG SCREENING (PREDICITION OF ACTIVITY, TOXICITY…)
- DRUG DESIGN (3D STRUCTURE, DRUG-PROTEIN INTERACTIONS, DE NOVO DESIGN…)
- POLYPHARMACOLOGY (DESIGNING MORE SPECIFIC OR MULTITARGET MOLECULES)
- DRUG REPURPOSING (IDENTIFICATION OF NEW TARGETS)
- CHEMICAL SYNTHESIS
HOW IS PHARMA INDUSTRY THINKING ABOUT ADDRESSING THE STATIC DRUG DISOVERY?
- USE THE SAME HEADCOUNT TO RUN MORE PROJECTS IN PARALLEL (INITIATE PROJECTS WITH LESS VALIDATION, ACCEPT A HIGH EARLY FAILURE RATE AND INITIALLY SUPERFICIAL SCIENCE)
- INVEST IN ASSAY TECHNOLOGY AND AUTOMATION
- INVEST IN AI
- DESIGN BETTER DISEASE MODELS
- MORE TEAMWORK (A RACE NOT A SERIES OF SPRINTS, NOT JUST INDIVIDUAL STAKEHOLDERS DOING THEIR PART AND LETTING IT OVER TO OTHERS)
- WORK WITH CLINICIANS TO UNDERSTAND PATIENT NEEDS AND CLINICAL DESIGN
- EARLY COLLABORATION WITH KEY OPINION LEAERS (KOLs) AND ENCOURAGE CONSTRUCTIVE CRITICISM
- DEVELOP BIOMARKERS TO SUPPORT TARGET ENGAGEMENT AND PATIENT STRATIFICATION AS PART OF RESEARCH PHASE
- CONTINUOUSLY CHALLENGE YOUR HYPOTHESES
HUMAN CRETIVITY + IMPROVED PROCESSES/TECHNOLOGY NEED TO BE COMBINED FOR SUCCESS!!!!
