|
|||||
|
|
Mutant-Selective Allosteric EGFR Degraders are Effective Against a Broad Range of Drug-Resistant Mutations |
|
| Authors: | Dr. Jaebong Jang Dr. Ciric To Dr. Dries J. H. De Clercq Dr. Eunyoung Park Charles M. Ponthier Bo Hee Shin Mierzhati Mushajiang Dr. Radosław P. Nowak Dr. Eric S. Fischer Dr. Michael J. Eck Dr. Pasi A. Jänne Dr. Nathanael S. Gray |
| Affiliation: | 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 Current address: College of Pharmacy, Korea University, 2511 Sejong-ro, Sejong, 30019 Republic of Korea These authors contributed equally to this work.;2. 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 These authors contributed equally to this work.;3. 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;4. 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 |
| 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: | allosteric combination treatment degrader drug-resistant mutation EGFR |