Osimertinib
Osimertinib mesylate
Precision oncology's poster child, designed to outsmart drug resistance.
Designed to defeat the mutation that defeats other cancer drugs.
Key Facts
- 1Generates over $5 billion in annual sales, AstraZeneca's top-selling drug
- 2Specifically designed to target the T790M resistance mutation in EGFR
- 3Uses a covalent "warhead" that forms a permanent bond with a cysteine residue
- 4Spares wild-type EGFR, dramatically reducing skin rash and diarrhoea
- 5Crosses the blood-brain barrier, treating brain metastases that other EGFR drugs miss
The Problem
Why This Molecule Was Needed
In 10-15% of Western patients and up to 50% of Asian patients, non-small cell lung cancer (NSCLC) is driven by activating mutations in the epidermal growth factor receptor (EGFR). First-generation EGFR inhibitors (gefitinib, 2003; erlotinib, 2004) produced dramatic tumour responses, but within 9 to 14 months virtually every patient developed resistance.
The most common culprit (~60% of cases) was the T790M "gatekeeper" mutation: a threonine-to-methionine substitution at the entrance to the ATP-binding pocket. The bulkier methionine side chain sterically clashes with first-gen drugs, reducing their binding affinity by 10 to 100 fold. The oncology community needed a drug specifically designed to overcome T790M resistance.
The Discovery
How It Happened
AstraZeneca launches the T790M programme
AstraZeneca begins a focused effort to design a third-generation EGFR inhibitor: potent against T790M, active against common activating mutations (Del19, L858R), and selective against wild-type EGFR to avoid the skin toxicity of earlier drugs.
Discovery of AZD9291 (osimertinib)
After screening covalent inhibitor libraries and extensive SAR optimisation, the team identifies AZD9291, combining a pyrimidine hinge binder, an indole for the hydrophobic pocket, and an acrylamide warhead that bonds covalently to Cys797.
Phase I: remarkable responses
The first-in-human AURA trial shows 61% objective response rates in T790M-positive patients, with responses also seen in patients with brain metastases.
Accelerated FDA approval
The FDA grants accelerated approval for osimertinib as second-line treatment of T790M-positive NSCLC, just 2.5 years from first-in-human dosing.
FLAURA: the first-line breakthrough
The FLAURA trial shows osimertinib nearly doubles progression-free survival versus first-gen drugs as first-line treatment (18.9 vs 10.2 months). It becomes the global standard of care for EGFR-mutant NSCLC.
The Molecule
Up Close
Tap any region or group card to explore key structural features.
The Takeaway
Designing around resistance with covalent selectivity
Osimertinib is a textbook example of rational drug design. The team started with a specific resistance mechanism (T790M), identified a molecular strategy (covalent binding to Cys797 with wild-type selectivity), and optimised systematically. A single functional group, the basic amine added for solubility, also enabled brain penetration, turning a resistance drug into a first-line standard of care.
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