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Small molecule EGFR inhibitors such as gefitinib and erlotinib have demonstrated clinical efficacy in the treatment of EGFR mutation positive non-small cell lung cancer (NSCLC) after disappointing earlier results with these agents in unselected patient populations. These mutations of EGFR are commonly referred to as sensitising or activating mutations. However, resistance to these drugs is commonly observed through an acquired EGFR T790M secondary mutation, known as the gatekeeper mutation. Osimertinib is the first inhibitor approved by the US FDA to selectively target the T790M resistant mutant whilst sparing the wildtype form of the enzyme. Essential to the discovery of this drug was the focused structure-driven computational and medicinal chemistry design strategy and synthetic chemistry innovation. The focused design work and clear clinical hypothesis resulted in rapid progress of the project with …