2. Academic Validation
  3. Mutant-Selective Allosteric EGFR Degraders are Effective Against a Broad Range of Drug-Resistant Mutations

Mutant-Selective Allosteric EGFR Degraders are Effective Against a Broad Range of Drug-Resistant Mutations

  • Angew Chem Int Ed Engl. 2020 Aug 17;59(34):14481-14489. doi: 10.1002/anie.202003500.
Jaebong Jang 1 2,  Ciric To 3,  Dries J H De Clercq 1,  Eunyoung Park 1,  Charles M Ponthier 1,  Bo Hee Shin 3,  Mierzhati Mushajiang 3,  Radosław P Nowak 1,  Eric S Fischer 1,  Michael J Eck 1,  Pasi A Jänne 3 4,  Nathanael S Gray 1
Affiliations

Affiliations

  • 1 Department of Cancer Biology, Dana-Farber Cancer Institute, Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Longwood Center, 360 Longwood Avenue, Boston, MA, 02215, USA.
  • 2 Current address: College of Pharmacy, Korea University, 2511 Sejong-ro, Sejong, 30019, Republic of Korea.
  • 3 Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Department of Medical Oncology, Dana-Farber Cancer Institute, Department of Medicine, Harvard Medical School, Longwood Center, 360 Longwood Avenue, Boston, MA, 02215, USA.
  • 4 Belfer Center for Applied Cancer Science, Longwood Center, 360 Longwood Avenue, Boston, MA, 02215, USA.
PMID: 32510788 DOI: 10.1002/anie.202003500
Abstract

Targeting epidermal growth factor receptor (EGFR) through an allosteric mechanism provides a potential therapeutic strategy to overcome drug-resistant EGFR mutations that emerge within the ATP binding site. Here, we develop an allosteric EGFR degrader, DDC-01-163, which can selectively inhibit the proliferation of L858R/T790M (L/T) mutant Ba/F3 cells while leaving wildtype EGFR Ba/F3 cells unaffected. DDC-01-163 is also effective against osimertinib-resistant cells with L/T/C797S and L/T/L718Q EGFR mutations. When combined with an ATP-site EGFR inhibitor, osimertinib, the anti-proliferative activity of DDC-01-163 against L858R/T790M EGFR-Ba/F3 cells is enhanced. Collectively, DDC-01-163 is a promising allosteric EGFR degrader with selective activity against various clinically relevant EGFR mutants as a single agent and when combined with an ATP-site inhibitor. Our data suggests that targeted protein degradation is a promising drug development approach for mutant EGFR.

Keywords

EGFR; allosteric; combination treatment; degrader; drug-resistant mutation.

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