Administration of single-agent epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) is a standard treatment option for metastatic non-small cell lung carcinomas with EGFR exon 19 deletions (ex19del) and L858R substitutions. However, there is a significant interpatient heterogeneity with regard to the degree of the response and its duration. Patients with EGFR ex19del mutation, TP53 wild-type, good performance status, low tumor burden and no circulating tumor DNA (ctDNA) at baseline have the best chances to derive pronounced benefit from TKI therapy. In contrast, subjects with EGFR L858R substitution, mutated TP53, poor overall condition, high tumor volume and detectable ctDNA are generally poor responders to EGFR inhibitors. ctDNA dynamics in the first days or weeks of treatment allows reliable identification of patients, who are very unlikely to derive clinically meaningful benefit from single-agent TKIs. These patients are candidates for clinical trials, which may involve the addition of chemotherapy and antiangiogenic drugs to patients, who failed to achieve immediate benefit from TKI monotherapy.

01 Sep 2024·European Journal of Medicinal Chemistry

Discovery of new cyclopropane sulfonamide derivatives as EGFR inhibitors to overcome C797S-mediated resistance and EGFR double mutation

Article

Author: Wu, Feng ; Cao, Longcai ; Ren, Yuanyuan ; Yan, Ming ; Li, Jianheng ; Yao, Han ; Li, Xingshu ; Liu, Jiadai

The C797S mutation of EGFR leads to Osimertinib resistance by blocking the covalent binding of Cys797. To develop new agents that can overcome EGFR mutation resistance, thirty seven new cyclopropane sulfonamide derivatives were synthesized and evaluated as EGFR^{L858R/T790M/C797S} or EGFR^{Del19/T790M/C797S} inhibitors by structure-based screening. Most of the synthesized compounds exhibit good to excellent anti proliferation activity against to BaF3-EGFR ^{L858R/T790M/C797S} and BaF3-^{C797S/Del19/T790M} cancer cell lines. Representative compounds 8l showed inhibitory activity against the two cancer cell lines with the IC₅₀ values of 0.0012 and 0.0013 μM, respectively. Another compound 8h, exhibited slightly lower activity (0.0042 and 0.0034 μM of the IC₅₀ values) to both of the two tri-mutation cell lines, but excellent activities against H1975 and PC9 cells with IC₅₀ values of 13 and 19 nM, respectively. Considering the acquired drug resistance of tumors is a gradual process, we chose 8h for further in vivo and mechanism study. 8h was demonstrated significantly inhibited tumor growth with 72.1 % of the TGI in the BaF3/EGFR-TM xenograft tumor model and 83.5 % in the H1975-DM xenograft tumor model. Compound 8h was confirmed to be safe with no significant side effects as showed by the results of in vitro assay of human normal cells and the sections of animals major organs. Mechanism studies showed that in addition to inhibiting EGFR mutations, 8h can also target the tumor microenvironment and induce tumor cell apoptosis. All these results indicate that 8h deserves further investigation as an EGFR inhibitor to overcome C797S-mediated resistance.

21 Jun 2024·Science Advances

In silico transcriptome screens identify epidermal growth factor receptor inhibitors as therapeutics for noise-induced hearing loss

Article

Author: Lovas, Sándor ; Diers, Jack ; Ryan, William G ; McCullumsmith, Robert E ; Imami, Ali Sajid ; Zallocchi, Marisa ; Dabestani, Parinaz Jila ; Li, Yuju ; Nguyen, Cassidy ; Vijayakumar, Sarath ; Rhoda, Lauren M ; Fleegel, Jonathan ; Zuo, Jian ; Hamoud, Abdul-Rizaq Ali ; DiGuiseppi, Joseph A ; Quevedo, Rene Vielman ; Tu, Shu

Noise-induced hearing loss (NIHL) is a common sensorineural hearing impairment that lacks U.S. Food and Drug Administration–approved drugs. To fill the gap in effective screening models, we used an in silico transcriptome-based drug screening approach, identifying 22 biological pathways and 64 potential small molecule treatments for NIHL. Two of these, afatinib and zorifertinib [epidermal growth factor receptor (EGFR) inhibitors], showed efficacy in zebrafish and mouse models. Further tests with EGFR knockout mice and EGF-morpholino zebrafish confirmed their protective role against NIHL. Molecular studies in mice highlighted EGFR’s crucial involvement in NIHL and the protective effect of zorifertinib. When given orally, zorifertinib was found in the perilymph with favorable pharmacokinetics. In addition, zorifertinib combined with AZD5438 (a cyclin-dependent kinase 2 inhibitor) synergistically prevented NIHL in zebrafish. Our results underscore the potential for in silico transcriptome-based drug screening in diseases lacking efficient models and suggest EGFR inhibitors as potential treatments for NIHL, meriting clinical trials.

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Indication	Highest Phase	Country/Location	Organization	Date
Non-Small Cell Lung Cancer	Preclinical	JP	Kanazawa University	11 Jan 2022

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