EGFR C797S + EGFR T790M + EGFR L858R

Ramucirumab plus osimertinib demonstrated encouraging safety and antitumor activity in T790M-positive EGFR-mutant NSCLC.

Compound 27 also exhibited good microsomes stabilities in human, rat and mouse liver species, but low bioavailability. This work would be very useful for discovering new quinazoline derivatives as tyrosine kinase inhibitors targeting triple mutant L858R/T790M/C797S.

Selective N-methylation of the H-bond accepting nitrogen ablates inhibitor potency, confirming the role of the K745 H-bond in potent, non-covalent inhibition of C797S variant. Insights from these studies offer new strategies for developing next generation inhibitors targeting EGFR in non-small cell lung cancer.

Furthermore, crystal structure analysis suggested that CH7233163 is a non-covalent ATP competitive inhibitor for EGFR-Del19/T790M/C797S that utilizes multiple interactions with the EGFR's αC-helix-in conformation to achieve potent inhibitory activity and mutant selectivity. Therefore, we conclude that CH7233163 is a potentially effective therapy for osimertinib resistant patients, especially in cases of EGFR-Del19/T790M/C797S.

According to our computational simulation, the results supported the experimental models and, therefore, could confirm and predict the molecular mechanism of drug efficacy.

Our findings indicate that the EGFR 19Del subtypes affect the clinical outcomes and resistance mechanisms to osimertinib in T790M-positive patients. Identifying patients with relatively worse treatment outcomes may be informative for establishing new therapies for these patients.

BI-4020 potently inhibits the above described EGFR variants and induces tumor regressions in a cross-resistant EGFRdel19 T790M C797S xenograft model. Key was the identification of a highly selective but moderately potent benzimidazole followed by complete rigidification of the molecule through macrocyclization.

EGFR mutation is one of the primary reasons for the emergence of resistance after treatment with the third-generation EGFR inhibitors such as AZD9291, CO1686 and Olmutinib. Furthermore, 12e exhibited good growth inhibition activity, induced G1 phase cell cycle arrest and apoptosis in BaF3/EGFR cells by suppressing EGFR phosphorylation signaling pathway. In all, our study might provide a novel structural design method and lay the solid foundation for the development of the 4th generation EGFR inhibitors.

In addition, compound 9h exhibits weak anti-proliferative effects on other tumor cells (HepG2, MCF-7, HT-29 and A431) and has lower toxic effect on HUVEC cells than AZD9291 (positive control)...Cell cycle analysis reveals that compound 9h suppresses the proliferation of cells by inducing cell cycle arrest in G0-G1 phase. The result of HS release evaluation suggests that the HS release of compound 9h is significantly more and faster than other compounds.

Per-residue energy-based hierarchical clustering analysis suggests that three hot-spot residues, L718, K745, and D855, are the key in achieving optimal binding modes for 25g with higher affinity in the EGFR compared to 25a. This study provides a rationale for the superior EGFR-inhibitory potency exhibited by 25g over 25a, which is expected to be useful for the future rational structure-based design of novel EGFR inhibitors with improved potency and selectivity.

Background: 1st generation (erlotinib & gefitinib), 2nd generation (afatinib), and 3rd generation (osimertinib) EGFR TKIs have marked efficacy in patient with EGFR-mutant NSCLC. Our results suggest that JNJ-372 will provide potential and effective therapeutic options for patients with no therapeutic option to overcome broad-spectrum of acquired resistance to EGFR-TKIs.

BRAF fusion had low frequency in lung cancer and occurred at different stage during disease development. BRAF inhibitors maybe a potential strategy for BRAF fusion lung cancers. As TKIs resistance mechanism, BRAF fusion is a huge clinical challenge, indicate the importance of further research.

Combination therapy with osimertinib and gefitinib is tolerable for first-line treatment of EGFR-mutated NSCLC and resulted in rapid plasma clearance of the EGFR mutation. The observed ORR is consistent with previously reported first-line response rates to osimertinib. Analysis of survival outcomes and acquired resistance mechanisms are pending data maturity and will facilitate understanding of the role of first-line dual EGFR TKI therapy for this pt population.