Tarloxotinib bromide (TH-4000) is an irreversible inhibitor prodrug of EGFR/HER2. In the hypoxic microenvironment of breast tumors (< 0.1% O2), Tarloxotinib bromide is converted into TH-4000E. TH-4000E inhibits the phosphorylation of HER2 dimers and downstream pathways, inducing apoptosis in HER2-positive breast cancer cells through a ROS-dependent mechanism[1-4].
Tarloxotinib bromide (0-10μM; 2h) inhibited pEGFR with IC50 of 201 nM in A431 cell. This suggests that tarloxotinib is much less effective against EGFR, HER2 and HER4 in cells to avoid generating any targeting activity in non-tumor tissues[1].
Tarloxotinib bromide(50 mg/kg, in 20% m/v 2-hydroxypropyl-b-cyclodextrin; i.p; once a week for 21 day) inhibits the growth of HCC-1954 tumors in mice and demonstrates greater efficacy than lapatinib in trastuzumab-resistant breast tumors. Tarloxotinib bromide also reduces the Ki67-positive zone, indicating decreased cell proliferation[2].
References:
[1]. Estrada-Bernal A, Le AT, et,al. Tarloxotinib Is a Hypoxia-Activated Pan-HER Kinase Inhibitor Active Against a Broad Range of HER-Family Oncogenes. Clin Cancer Res. 2021 Mar 1;27(5):1463-1475. doi: 10.1158/1078-0432.CCR-20-3555. Epub 2020 Dec 22. PMID: 33355298; PMCID: PMC7926264.
[2]. Shao X, Yang D, et,al. TH-4000, a hypoxia-activated pan-HER inhibitor, shows excellent preclinical efficacy for the treatment of HER2+ breast cancer. Arch Toxicol. 2024 Mar;98(3):865-881. doi: 10.1007/s00204-023-03670-6. Epub 2024 Jan 11. PMID: 38212449.
[3]. Maddox AL, Brehove MS, et,al. Molecular Assessment of HER2 to Identify Signatures Associated with Therapy Response in HER2-Positive Breast Cancer. Cancers (Basel). 2022 Jun 4;14(11):2795. doi: 10.3390/cancers14112795. PMID: 35681773; PMCID: PMC9179327
[4].Phillips RM. Targeting the hypoxic fraction of tumours using hypoxia-activated prodrugs. Cancer Chemother Pharmacol. 2016 Mar;77(3):441-57. doi: 10.1007/s00280-015-2920-7. Epub 2016 Jan 25. PMID: 26811177; PMCID: PMC4767869.
Tarloxotinib bromide (TH-4000)是一种不可逆的EGFR/HER2抑制剂前体。在乳腺肿瘤缺氧微环境下(O2 < 0.1%)， Tarloxotinib bromide转化为TH-4000E。TH-4000E抑制HER2二聚体磷酸化及其下游通路，通过ROS依赖机制诱导HER2阳性乳腺癌细胞凋亡[1-4]。
Tarloxotinib bromide (0-10μM; 2h)抑制A431细胞pEGFR, IC50为201 nM。这表明Tarloxotinib bromide对细胞中的EGFR、HER2和HER4的有效性要低得多，以避免在非肿瘤组织中产生任何靶向活性[1]。
Tarloxotinib bromide (50 mg/kg, in 20% m/v 2-hydroxypropyl-b-cyclodextrin; i.p; once a week for 21 day)抑制小鼠HCC-1954肿瘤的生长。Tarloxotinib bromide治疗trastuzumab耐药乳腺肿瘤比lapatinib更有效。Tarloxotinib bromide降低了Ki67(marker of cell proliferation)阳性区[2]。