Mobocertinib mesylate

Mobocertinib (TAK-788) mesylate is an orally active and irreversible EGFR/HER2 inhibitor. Mobocertinib mesylate potently inhibits oncogenic variants containing activating EGFRex20ins mutations with selectivity over wild-type EGFR. Mobocertinib mesylate can be used in NSCLC research[1][2].

Research Areas >> Cancer

Signaling Pathways >> JAK/STAT Signaling >> EGFR

Signaling Pathways >> Protein Tyrosine Kinase/RTK >> EGFR

HER2

EGFR exon 20 insertion

EGFR (WT)

Mobocertinib mesylate (1.5 nM-10 μM; 7 days) inhibits LU0387 (NPH) cells with IC50 of 21 nM[1]. Mobocertinib mesylate (2 h) potently inhibits EGFR with common activating mutations (HCC827 (D), HCC4011 (L)) or with a T790M mutation (H1975 (LT)) more potently than WT EGFR (A431 (WT))[1]. Mobocertinib mesylate (0.1 nM-1 μM; 6 h) inhibits pEGFR and pERK1/2 in CUTO14 (ASV) cells[1]. Mobocertinib mesylate (0.3 nM-1 μM; 6 h) inhibits EGFR and downstream signaling[1]. Mobocertinib mesylate (0.01, 0.1 and 1 μM; 6 h) inhibits HER2 signaling in H1781 (HER2 Exon 20G776>VC), Ba/F3 (HER2 exon 20YVMA) cells[2]. Cell Viability Assay[1] Cell Line: LU0387 (NPH) cells Concentration: 1.5 nM-10 μM Incubation Time: 7 days Result: Showed good inhibition activity for LU0387 (NPH) cells with IC50 of 21 nM. Cell Viability Assay[1] Cell Line: A431 (WT), HCC827 (D), HCC4011 (L), H1975 (LT) cells Concentration: Incubation Time: 2 h Result: Inhibited EGFR with common activating mutations of HCC827 (D), HCC4011 (L) cells and T790M mutation of H1975 (LT) with IC50s of 4, 1.3 and 9.8 nM respectively, which more potently than WT EGFR (A431 (WT); IC50 of 35 nM). Western Blot Analysis[1] Cell Line: CUTO14 (ASV) cells Concentration: 0.1 nM-1 μM Incubation Time: 6 h Result: Robustly inhibited EGFR signaling, reaching 80% and 100% inhibition of phosphorylated EGFR (pEGFR) at concentrations of 100 nM and 1 μM, respectively. Western Blot Analysis[1] Cell Line: HCC827 (D), HCC4011 (L), H1975 (LT) cells Concentration: 0.3 nM-1 μM Incubation Time: 6 h Result: Potently inhibited EGFR and downstream signaling in HCC827 (D), HCC4011 (L) and H1975 (LT) cells. Western Blot Analysis[2] Cell Line: H1781 (HER2 Exon 20G776>VC), Ba/F3 (HER2 exon 20YVMA) cells Concentration: 0.01, 0.1 and 1 μM Incubation Time: 6 h Result: Inhibited HER2 signaling in H1781 and Ba/F3-HER2 exon 20YVMA mutant cells at 0.1 μM with significantly decreased phosphorylations of HER2, AKT, and ERK1/2 in a dose-dependent manner.

Mobocertinib mesylate (3, 10, 30 mg/kg; p.o.; once daily for 20 days) significantly induces tumor growth inhibition[1]. Animal Model: Animal model: Female Athymic Nude-Foxn1nu mice (human NSCLC H1975 LT tumor model)[1]. Dosage: 3, 10, 30 mg/kg Administration: Oral; once daily for 20 days. Result: Decreased the mean tumor volume by 44% and 92% when at 3 mg/kg and 10 mg/kg, respectively, relative to the tumor size of vehicle group. Induced a 76% tumor regression relative to the pretreatment tumor size at 30 mg/kg.

[1]. Gonzalvez F, et al. Mobocertinib (TAK-788): A Targeted Inhibitor of EGFR Exon 20 Insertion Mutants in Non-Small Cell Lung Cancer. Cancer Discov. 2021 Jul;11(7):1672-1687.

[2]. Han H, et al. Targeting HER2 Exon 20 Insertion-Mutant Lung Adenocarcinoma with a Novel Tyrosine Kinase Inhibitor Mobocertinib. Cancer Res. 2021 Oct 15;81(20):5311-5324.