W5 L4 - Cancer Drugs ** Flashcards
(10 cards)
What are the major categories of cancer therapeutics?
Cancer treatments include hormonal therapies, immunotherapies (e.g., checkpoint inhibitors, CAR T cells), biologics (e.g., mAbs, ADCs), and chemotherapies (e.g., alkylating agents, anti-metabolites, topoisomerase inhibitors, microtubule inhibitors).
What makes a drug efficacious and safe in preclinical development?
Must demonstrate good ADME: absorption, distribution, metabolism, excretion.
Should interact effectively with target proteins while minimizing off-target effects.
Evaluated using in vitro assays, PK profiling across species, and toxicology in animal models.
What advances have transformed drug discovery since the 1990s?
Improved biological understanding and genetic insight.
High-throughput and reduced-animal in vitro testing.
Enhanced structural data for SAR design.
Better PK modeling and computational predictions.
What is EGFR and why is it significant in cancer?
EGFR is a receptor tyrosine kinase involved in cell growth signaling.
Its overactivation (via mutation or overexpression) contributes to carcinogenesis, particularly in lung cancer.
How do first-generation EGFR inhibitors work and why are they limited?
Inhibit mutated EGFR, effective in a subset of NSCLC patients.
Resistance arises from additional mutations (e.g., T790M).
Toxicity arises due to inhibition of WT EGFR in healthy tissue.
How does the T790M mutation lead to drug resistance?
Enhances ATP binding and reduces drug affinity, diminishing drug efficacy.
Leads to decreased sensitivity to first-generation inhibitors.
What challenges exist in designing drugs for EGFR T790M mutations?
Irreversible inhibitors can overcome resistance but often lack selectivity.
Key is designing drugs with high potency for T790M, minimal WT activity, and suitable pharmacokinetics.
Why is lipophilicity (logD) a critical parameter in drug design?
Affects solubility, permeability, metabolism, and toxicity.
Needs to be optimized to balance efficacy and pharmacokinetic properties.
What trade-offs are involved in optimizing a drug candidate?
Balancing potency, selectivity (DM vs. AM/WT), and ADME properties.
Minor changes in structure can significantly affect activity and drug-likeness.
How was a successful EGFR T790M inhibitor (e.g., AZD9291/Tagrisso) developed?
Achieved selectivity and tolerability by careful structural optimization.
Demonstrated robust tumour reduction and long-lasting target inhibition.
