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

Angewandte Chemie - Tập 132 Số 34 - Trang 14589-14597 - 2020
Jaebong Jang1,2,3, Ciric To4,3, Dries J.H. De Clercq2, Eunyoung Park2, Charles M. Ponthier2, Bo Hee Shin4, Mierzhati Mushajiang4, Radosław P. Nowak2, Eric S. Fischer2, Michael J. Eck2, Pasi A. Jänne5,4, Nathanael S. Gray2
1Current address: College of Pharmacy, Korea University, 2511 Sejong-ro, Sejong, 30019 Republic of Korea
2Department 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
3these authors contributed equally to this work
4Lowe 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
5Belfer Center for Applied Cancer Science, Longwood Center, 360 Longwood Avenue, Boston, MA, 02215 USA

Tóm tắt

AbstractTargeting 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.

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Angewandte Chemie

Tập 132 Số 34

14589-14597

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