This document discusses the process of cancer drug discovery and development from target identification to clinical trials. It begins with an overview of the hallmarks of cancer and current chemotherapeutic drugs. The drug discovery process is then outlined, including target identification and validation, hit to lead identification through screening, lead optimization, preclinical testing, IND application, and clinical trials through Phases I-III to evaluate safety, efficacy, and obtain approval. Natural products are highlighted as an abundant source of existing anticancer compounds.

1. Cancer Drug Discovery
and Development
Syamprasad NP

2. Hallmarks
of Cancer
Sustained
proliferative
signaling
Enabling
replicative
immortality
Evading
growth
suppressors
Resistance to
cell death
Avoiding
immune
destruction
Angiogenesis
Activating
Invasion and
Metastasis
Deregulated
cellular
energetics
Tumor
promoting
inflammation
Hall marks of cancer cell lines
Adaptive
Metabolic
Inflammatory Proliferative
Anti-apoptotic

3. Chemotherapeutic drugs
 Alkylating agents : Chlorambucil, Cyclophosphamide
 Antimetabolites : Methotrexate, 5-fluorouracil
 Mitotic inhibitors : Vincristine, Paclitaxel
 Antibiotics : Actinomycin D, Doxorubicin
 Nitrosoureas : Carmustine , Lomustine
 Antibody : Trastazumab , Bevacizumab
 Enzyme : Asparaginase
 DNA synthesis inhibitors : Hydroxyurea
 DNA damaging agents : Cisplatin, Oxaliplatin

4. Chemotherapeutic drugs
 Signal transduction inhibitor : imatinib , sorafinib
 Differentiation agent : all-trans retinoic acid, HDAC inhibitors
 Hormones and hormone antagonists: tamoxifen, Aromatase inhibitors
 Proteasome inhibitors : Bortezomib (Velcade)
 DNA topoisomerase I inhibitors : Camptothecin, Irinotecan
 Agents that inhibit DNA repair : PARP inhibitors
 Arsenic trioxide : Degradation of the PML-RAR oncoprotein
 Inhibitors of DNA methylation : Zebularin, azacitidine
 Chimeric toxic protein : Ontak (IL2 + Diphtheria toxin)

5. Why cancer drug discovery?
Unmet medical need - Here we start drug discovery
All chemotherapeutic drugs fail to treat late stage cancer
Resistance

6. Drug discovery process
www.doctortarget.com

7. Target identification
What is a drug target?
A drug target is the specific binding site of a drug in vivo through which the drug exerts its
action
 The drug target is a biomolecule(s)
 It should have special sites were endogenous or exogenous (chemical molecules)
substances can bind
 The biomolecular structure might change when small molecules bind to them
 Change in the biomolecule’s structure should modulate various physiological
responses
 The expression, activity, and structure of the biomolecule might change over the
duration of the pathological process
Characteristics

8. Established targets: are those for which there is a good scientific understanding,
supported by a lengthy publication history, of both how the target functions in
normal physiology and how it is involved in human pathology
New Target: are all those targets that are not "established targets" but which
have been or are the subject of drug discovery campaigns. These typically include
newly discovered proteins, or proteins whose function has now become clear as
a result of basic scientific research.
Selection of Target

9. Target validation
Animal model of disease
Expression
profile
Biomarker
Cell based disease model Pharmacological tool compounds
Functional analysis
Genetic
manipulation
Disease association genetics
Target
validation
methods

10. Hit to Lead Identification
Hit compounds has some structural activity relationship against the chosen
target, but not yet good enough to be the drug itself
High Throughput Screening- Selection of Lead molecules from Hits
Identify the “pharmacophore” directly responsible for activity and optimize
structure to improve interactions with target (Lead optimization)
Natural products Synthetic Chemistry Biologicals
Sources

11. • Vincristin
• Vinblastin
• Topothecan
• Irinothecan
• Etoposide
• Paclitaxel
• Docetaxel
• Noscapine
• Cannabinol
• Bleomycin
• Doxorubicin
• Donourubicin
• Mitomycin C
• Actinomycin D
• Neocarzinstatin
• Kedarzidin
• Cytarabine
• Trabectedine
• Eribulin
Nature is a abundant source of anticancer agents
• Curcumin - Turmeric
• Eucalyptin - Eucalyptus
• Piperine - Black pepper
• Piper longumine- Long pepper
• 6-gingerol - Ginger
• Thymoquinone - Black Cumin
• Eugenol - Clove
• Capsaicin - Red chili pepper
• Diallyl disulfide - Garlic
• Crocin - Saffron
• Carnosic acid - Rosemary
• Cinnamaldehyde- Cinnamon
• β-caryophyllene - Origano
Approved drugs Anticancer molecules in spices

12. Lead to candidate
Stability Genotoxicity
Metabolism PK/PD

13. Lead to candidate
Preclinical toxicity
Acute- single dose 14 days
Repeated-28 days
Repeated-90 days
Chronic toxicity-6 months
Developmental toxicity
F1 generation toxicity
F2 generation toxicity
Candidate Molecule

14. IND application and Initiation of Clinical Trial
FDA
Sponsor (e.g. Pharma, NIH, WHO, etc.)
Contract/Clinical Research Organization (CRO)
Medical
Director
Project
Manager
Clinical Research
Associate (CRA)
Regulatory
Personnel
Investigator
Sub-Investigator
IRB / IEC
Clinical Research Coordinator
Study Subjects (patients)
Investigators meeting
Informed consent

15. Clinical Trial
1-2 yrs
Hundreds-
thousands
Subjects with
indications
New indications,
QoL, surveillance
IV
2-3 yrs
Hundreds-
thousands
Subjects with
indications
Safety & efficacy
Basis for labeling,
new formulations
III
1-2 yrs
Several
hundred
Subjects with
indications
Short-term side
effects & efficacy
II
6-12 mos
20-80
Healthy
volunteers
Safety, ADME,
bioactivity,
drug-drug interaction
I
Length
(per
phase)
Scope
Subjects
Purpose
Phase
Drug
Molecule

16. Thank You…
syamprasadnp9746@gmail.com