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

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.

Targeting the Epidermal Growth Factor Receptor with Molecular Degraders: State-of-the-Art and Future Opportunities

“…An in vitro cell permeability experiment confirmed that the antiproliferative activity of the PROTAC was dependent on the ligand inhibitory activity and cell permeability. Further, the degradation and antiproliferative activity potentiated with the combination of osimertinib, which concluded that the combination therapy of EGFR-TKI with PROTAC might be an effective strategy in future cancer treatment . In this rapidly growing EGFR-PROTACs development journey, autophagy mediated degradation of EGFR further added a new direction in the targeted protein degradation field.…”

“…151 In addition, 25a precursor (94) was synthesized by amination with 72 by the free amino group of the PEG linker (92). 160 Further, these precursor molecules (90 and 94) were coupled with EGFR inhibitors (91 and 24) to yield the corresponding PROTACs (16 and 25a) (Figure 15).…”

“…Further, the degradation and antiproliferative activity potentiated with the combination of osimertinib, which concluded that the combination therapy of EGFR-TKI with PROTAC might be an effective strategy in future cancer treatment. 160 135 Later, an irreversible EGFR inhibitor, canertinib (29)-based PROTACs, which contains the pomalidomide E3L ligand emerged and it effectively degraded EGFR L858R/T790M . The alkyl chain containing pomalidomide-based PROTACs SIAIS125 (30) and SIAIS126 (31) (Figure 9B) effectively degraded EGFR L858R/T790M in the H1975 cell line with DC 50 values of 50 nM and 30 nM, respectively.…”

“…The fourth generation EGFR inhibitor EAI001 (99) was modified to 24 by attaching 1-(pyridin-2-yl)piperazine to the isoindolinone moiety to extend the solvent-exposed area for the development of 25a (Figure 17A). 160 Further, E3L ligand modification also affects the antiproliferative and degradation activity of the PROTACs molecules. By modifying the VHL ligand, 34 showed better inhibitory and degradation activity than 35, which has the same EGFR warhead and linker.…”

Allosteric Inhibition of the Epidermal Growth Factor Receptor

“…Second- and third-generation TKIs such as afatinib (BIBW-2992), , rociletinib (CO-1686), , WZ-4002, and osimertinib (AZD-9291) − target the more drug-resistant variant L858R/T790M EGFR by irreversibly alkylating a conserved active site cysteine side chain (C797). Monoclonal antibodies and small molecules that interact directly with EGFR can also be engineered to induce EGFR degradation via either proteasomal − or lysosomal pathways.…”