Ceritinib

Wang Y, et al. Toxicology and Applied Pharmacology, 2025, 117489.

Ceritinib, an IGF1R-targeting tyrosine kinase inhibitor, was experimentally applied to investigate its antitumor efficacy in laryngeal squamous cell carcinoma (LSCC). LSCC cell lines (TU686, AMC-HN8) were treated with Ceritinib, revealing dose-dependent inhibition of proliferation. Mechanistically, Ceritinib induced ROS accumulation, mitochondrial membrane potential (MMP) loss, and oxidative stress. N-acetylcysteine (NAC) abrogated these effects, confirming ROS-dependent apoptosis. Transcriptomic and Western blot analyses demonstrated downregulation of PI3K/Akt signaling. Chou-Talalay analysis verified synergism between Ceritinib and cisplatin, enhancing mitochondrial dysfunction and apoptotic activity. In vivo, Ceritinib (25 mg/kg), alone or with cisplatin (2 mg/kg), significantly suppressed tumor growth in xenograft models without affecting systemic toxicity. These results support Ceritinib's application as a mitochondrial apoptosis inducer in LSCC, particularly through ROS-mediated inhibition of PI3K/Akt signaling.

Zhou H, et al. European Journal of Medicinal Chemistry, 2024, 279, 116827.

A novel Ceritinib-based PROTAC, designated as 4B, was developed to address resistance in ALK-positive malignancies. Constructed by conjugating Ceritinib with thalidomide via a rigid linker, 4B demonstrated oral bioavailability (F = 14.22%) and potent in vitro and in vivo activity. In Karpas 299 cells, 4B induced sustained degradation of ALK fusion proteins (DC₅₀ = 119.33 nM, Dmax = 97.1%) and suppressed downstream signaling pathways. Anti-proliferative assays revealed comparable efficacy to Ceritinib (IC₅₀ = 3.11 ± 0.08 nM), with enhanced potency against the resistant G1202R mutation (IC₅₀ = 52.82 nM vs 109.5 nM). In vivo, oral administration of 4B achieved 49.5% tumor growth inhibition in Karpas 299 xenografts. This study underscores the therapeutic potential of rationally designed Ceritinib-based PROTACs for overcoming ALK inhibitor resistance in cancer therapy.

Li X, et al. iScience, 2024, 27(2), 109015.

To address acquired resistance to ceritinib in ALK-rearranged non-small cell lung cancer (NSCLC), researchers developed dEALK1, a bifunctional small-molecule degrader linking the ALK tyrosine kinase domain to the E3 ubiquitin ligase cereblon. dEALK1 was tested in vitro on NSCLC cells expressing either wild-type or ceritinib-resistant EML4-ALK mutants. Treatment with dEALK1 induced selective proteasomal degradation of both wild-type and mutant EML4-ALK, confirmed by immunoblotting. Cell viability assays demonstrated substantial growth inhibition and apoptosis in dEALK1-treated cells, compared to ceritinib alone. In vivo, dEALK1 effectively suppressed tumor growth in xenograft models harboring ceritinib-resistant EML4-ALK mutations. These results highlight dEALK1 as a promising therapeutic modality that leverages targeted protein degradation to circumvent ceritinib resistance in ALK-rearranged NSCLC.