Lazertinib

Lazertinib (YH25448; GNS-1480) is an orally active, blood-brain barrier permeable third-generation EGFR tyrosine kinase inhibitor, as well as an ABCB1/ABCG2 inhibitor and a TRPA1 activator. Lazertinib exhibits IC₅₀ values of 0.4 mM and 0.2 mM against human ABCB1 and ABCG2, respectively. By inhibiting mutant EGFR signaling, EGFR phosphorylation and the downstream ERK/AKT pathway, as well as upregulating surface expression of EGFR/MET, Lazertinib induces cell cycle arrest, apoptosis, spontaneous calcium responses, hyperexcitability of dorsal root ganglion (DRG) neurons, and TRPA1-dependent pain-like behaviors. Lazertinib competitively binds to the substrate-binding sites of ABCB1/ABCG2, stimulates their ATPase activity without altering their expression or plasma membrane localization, thereby enhancing ADCC activity, acting as a chemosensitizer, and reversing ABCB1-mediated multidrug resistance. It exerts antitumor activity as a single agent or in combination with other drugs. Lazertinib is applicable to research related to non-small cell lung cancer, multidrug-resistant cancers, and paresthesia^[1][2][3][4]. IC50 & Target:EGFR^[1] In Vitro:Lazertinib (0.1-1000 nM; 3 d) inhibits the viability of Ba/F3 cells expressing various rare EGFR mutations, with IC₅₀ values ranging from 3.5 nM to 108.3 nM^[1].
Lazertinib (10 nM (YUO-139 PDOs); 100 nM (YU-1092 PDCs); 72 h) upregulates EGFR expression on the surface of EGFR^G719S-mutant YUO-139 patient-derived organoids and EGFR^L861Q-mutant YU-1092 patient-derived cells after 72 h of treatment^[1].
Lazertinib (0.001-10 μM; 72 h) inhibits the viability of EGFR-mutant non-small cell lung cancer (NSCLC) cell lines after 72 h of incubation^[2].
Lazertinib (0.01-3.0 μM; 7 d, medium changed every 72 h) inhibits the long-term proliferation of PC-9 EGFR-mutant NSCLC cells in a concentration-dependent manner within 7 days, but fails to achieve complete growth inhibition at the tested concentrations^[2].
Lazertinib (100 nM; 4 h; 72 h) inhibits the phosphorylation of EGFR, ERK and AKT in PC-9 and HCC4011 EGFR-mutant NSCLC cells, but its inhibitory effects on ERK and AKT disappear by 72 h^[2].
Lazertinib (100 nM; 48 h) upregulates the expression of the anti-apoptotic protein MCL-1 in PC-9, HCC4011 and H1975 EGFR-mutant non-small cell lung cancer cells^[2].
Lazertinib (100 μM; 72 h) exhibits equivalent cytotoxicity in drug-sensitive parental cancer cell lines (HepG2, KB, S1, HEK293/Vector) and their multidrug-resistant (MDR) sublines with overexpressed ABCB1 or ABCG2. It reduces the IC₅₀ values of Vincristine (HY-N0488A), Doxorubicin (HY-15142A), Mitoxantrone (HY-13502), and Topotecan (HY-13768), respectively, but shows no significant effect on Cisplatin (HY-17394)^[3].
Lazertinib (0.1-1 μM; 24 h) does not induce neurite fragmentation in primary cultured dorsal root ganglion (DRG) neurons from the L3, L4 and L5 segments of adult mice^[4]. In Vivo:Lazertinib (10 mg/kg; p.o.; once daily; days 27-29) achieves 26.3% and 141% tumor growth inhibition in Ba/F3 EGFR^G719S and YUO-139 EGFR^G719S xenograft models of non-small cell lung cancer, respectively^[1].
Mesylate of Lazertinib (10 mg/kg; p.o.; once daily; for 19 consecutive days) fails to inhibit tumor growth in the gefitinib (HY-50895)-resistant non-small cell lung cancer EGFR^L861Q YU-1092 xenograft model^[1].
Mesylate of Lazertinib (10 mg/kg; p.o.; once daily; administered until day 29) induces initial tumor regression but fails to achieve durable control in the EGFR-TKI-resistant non-small cell lung cancer YHIM-1008 EGFR^G719C/S768I xenograft model^[1].
Mesylate of Lazertinib (3 mg/kg; daily; for 31 consecutive days) exerts transient anti-tumor activity in PC-9 CDX tumors, with the tumors exhibiting regrowth within 3 weeks after the initiation of treatment^[2].
Mesylate of Lazertinib (10 mg/kg; p.o.; once every 3 days; 6 doses total) fails to inhibit the growth of ABCB1-overexpressing HepG2/adr xenografts. However, when combined with Doxorubicin (HY-15142A), it effectively reverses ABCB1-mediated multidrug resistance, significantly reduces tumor volume and weight, with no observed toxicity^[3].
Mesylate of Lazertinib (1 mM, 20 μL; plantar injection; single administration) induces TRPA1-dependent pain-like behavior in male C57BL/6J mice, with an average licking and biting duration of 58.91 seconds within 15 minutes^[4].