Novel potent and selective fourth-generation inhibitors targeting EGFR for NSCLC therapy.

8622 Background: Epidermal growth factor receptor (EGFR)-activating mutations (Del19 or L858R) are oncogenic drivers of non-small cell lung cancer (NSCLC). Most patients treated with tyrosine kinase inhibitors (TKIs) will eventually develop resistance mutations including the T790M gatekeeper mutation. Osimertinib, a third-generation covalent TKI, is efficacious against the T790M resistance mutation and prevents its onset. However, treatment with Osimertinib inevitably induces additional mutations, especially the C797S mutation, as well as various off-target resistance mechanisms. To date, there are no approved therapies capable of overcoming mutational or non-mutational resistance to third-generation EGFR TKIs. Methods: We have characterized the efficacy of two novel fourth-generation EGFR inhibitors, CCM-205 and CCM-308, which are potent against both mutational and non-mutational tumor resistance to Osimertinib. Enzymatic binding affinities were determined by KdELECT assay. Cell-Titer-Glo (CTG) assay was used to assess cytotoxicity (cellular IC 50 ) of CCM-205 and CCM-308 in vitro on EGFR triple mutant and other Osimertinib-resistant cell lines, with comparison to both Osimertinib and fourth-generation EGFR inhibitor BLU-945. In vivo tumor growth inhibition (TGI) was determined in Osimertinib-resistant xenografts including the triple mutant PC9-DTC (Del19/T790M/C797S) model. Results: In Ba/F3 EGFR DTC and LTC cells, CCM-205 / CCM-308 inhibit proliferation with IC 50 s of 137 nM / 40 nM and 198 nM / 61 nM respectively, while Osimertinib antiproliferation is limited to 1.225 µM and 1.562 µM respectively. Moreover, CCM-205 / CCM-308 spare Ba/F3 EGFR WT better than Osimertinib with IC 50 s of 577 nM / 294 nM (182 nM for Osimertinib). CCM-205 / CCM-308 also bind tightly to double mutants targeted by Osimertinib with K d s for EGFR LT (L858R/T790M) of 4.9 nM / 1.2 nM. CCM-205 and CCM-308 are more potent against PC9 DTC cells (IC 50 s: 1.02 µM and 220 nM, respectively) than Osimertinib (4.10 µM) and are comparable to BLU-945 (559 nM). In addition, CCM-205 / CCM-308 are highly potent against Osimertinib-resistant PC9 (IC 50 s: 728 nM / 321 nM) and H1975 (IC 50 s: 1.716 µM / 684 nM) cell lines generated through 8-week treatment with 1 µM Osimertinib (Osimertinib IC 50 = 3.81 µM and 4.70 µM, respectively), while EGFR-specific fourth-generation inhibitors targeting C797S such as BLU-945 lose potency (IC 50 s: 7.96 µM and > 10 µM, respectively). In the PC9-DTC xenograft, CCM-205 completely inhibited tumor growth and induced tumor regression (> 100% TGI) exceeding that of BLU-945, while the tumor was resistant to Osimertinib (< 20% TGI), when agents were delivered orally at similar fractions of their maximum tolerated doses (MTDs). Conclusions: Novel fourth-generation EGFR inhibitors have been developed that can potentially overcome both on-target and off-target resistance in NSCLC and have potential clinical applications.

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