Title: “Mutant-selective allosteric EGFR inhibitors”
By David Scott
Organized by the Medicinal Chemistry Section
of the Northeastern Section, American Chemical Society (NESACS)
Thursday –June 16th, 2022
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Abstract: Targeted EGFR inhibitors have changed the treatment landscape for non-small cell lung cancer (NSCLC) patients, with third-generation covalent inhibitor osimertinib approved for first-line therapy in patients with activating L858R or del19 EGFR mutations. However, resistance mechanisms to osimertinib emerge over time. These include C797S which prevents covalent bond formation. There are no approved EGFR inhibitors with efficacy against the double (L858R/ C797S) or triple (L858R/ T790M/C797S) mutants and a clear unmet need exists for patients whose tumors progress to that stage. Allosteric EGFR inhibitors have been identified with potency against these osi-resistant mutants, and selectivity over wt EGFR, and they offer an alternative approach to another generation of ATP site inhibitors. DFCI has identified and optimized allosteric EGFR inhibitors from the isoindolinone series and pursued scaffold-hopping to develop compounds with potential to advance into the clinic.
Biography: Dr. David A Scott obtained his undergraduate degree from the University of St Andrews in his native Scotland, and a D Phil in organic chemistry from the University of Oxford in 2000, working with Professor George Fleet. Post-doctoral studies were conducted in the lab of Professor Philip Magnus at UT Austin, Texas. In 2002, he joined the oncology group at the AstraZeneca Boston site, where he led chemistry teams developing inhibitors of kinases and PARP enzymes. In 2013, he joined the Dana-Farber Cancer Institute, where he is the Director of the Medicinal Chemistry Core. The Core supports and collaborates with academic groups and their industry partners at DFCI and across the Longwood medical area on a diverse set of projects, target classes and disease indications.