Alectinib Hydrochloride is a potent, selective, and orally available ALK inhibitor with an IC50 value of 1.9nM and a Kd value of 2.4nM[1]. Alectinib Hydrochloride suppresses the L1196M-mutant ALK with an IC50 of 1.56nM[2]. Alectinib Hydrochloride increases the intracellular accumulation of ABCB1/ABCG2 substrates such as doxorubicin (DOX) and Rhodamine 123 (Rho 123) by inhibiting the efflux function of the transporters in ABCB1- or ABCG2-overexpressing cells, and stimulates ATPase activity and competed with substrates of ABCB1 or ABCG2[3]. Alectinib Hydrochloride has been widely used to inhibit the growth of lung cancer cells with ALK mutations[4].
In vitro, Alectinib Hydrochloride treatment for 48 hours significantly inhibited the proliferation of H2228 cells and ABC-11 cells, with IC50 values of 0.03μM and 0.13μM, respectively[5]. Treatment with 30nM Alectinib Hydrochloride for 48 hours significantly inhibited ALK-mediated neurite growth in PC12 cells[6]. Treatment with 10μM Alectinib Hydrochloride for 48 hours induced apoptosis in U87MG cells, inhibited the tyrosine phosphorylation of STAT3, and activated the tyrosine phosphorylation of Janus kinase 2 (JAK2)[7].
In vivo, Alectinib Hydrochloride treatment at a single dose of 50mg/kg via intraperitoneal injection for 24 hours significantly reduced cerebral infarction and neurological deficits in the ischemic stroke mouse model, as well as the loss of cerebral vascular integrity and damage to the blood-brain barrier[8]. Oral administration of 10mg/kg of Alectinib Hydrochloride daily for 4 weeks significantly inhibited tumor growth in a H3122 cell-xenograft mouse model, without affecting the body weight of the mice[9].
References:
[1] Madlool D T, Al-Ani I, Ata T, et al. Solubility, pH-Solubility Profile, pH-Rate Profile, and Kinetic Stability of the Tyrosine Kinase Inhibitor, Alectinib[J]. Pharmaceuticals, 2024, 17(6): 776.
[2] Song Z, Wang M, Zhang A. Alectinib: a novel second generation anaplastic lymphoma kinase (ALK) inhibitor for overcoming clinically-acquired resistance[J]. Acta Pharmaceutica Sinica B, 2015, 5(1): 34-37.
[3] Yang K, Chen Y, To K K W, et al. Alectinib (CH5424802) antagonizes ABCB1-and ABCG2-mediated multidrug resistance in vitro, in vivo and ex vivo[J]. Experimental & molecular medicine, 2017, 49(3): e303-e303.
[4] Yoshimura Y, Kurasawa M, Yorozu K, et al. Antitumor activity of alectinib, a selective ALK inhibitor, in an ALK-positive NSCLC cell line harboring G1269A mutation: efficacy of alectinib against ALK G1269A mutated cells[J]. Cancer chemotherapy and pharmacology, 2016, 77(3): 623-628.
[5] Isozaki H, Ichihara E, Takigawa N, et al. Non–small cell lung cancer cells acquire resistance to the ALK inhibitor alectinib by activating alternative receptor tyrosine kinases[J]. Cancer research, 2016, 76(6): 1506-1516.
[6] Alam M W, Borenäs M, Lind D E, et al. Alectinib, an anaplastic lymphoma kinase inhibitor, abolishes ALK activity and growth in ALK-positive neuroblastoma cells[J]. Frontiers in oncology, 2019, 9: 579.
[7] Kawauchi D, Takahashi M, Satomi K, et al. The ALK inhibitors, alectinib and ceritinib, induce ALK‐independent and STAT3‐dependent glioblastoma cell death[J]. Cancer Science, 2021, 112(6): 2442-2453.
[8] Hu Y, Chang L, Zhu Y, et al. Inhibition of anaplastic lymphoma kinase protects from ischemic stroke[J]. Stroke, 2024, 55(4): 1075-1085.
[9] Ando C, Ichihara E, Nishi T, et al. Efficacy of gilteritinib in comparison with alectinib for the treatment of ALK‐rearranged non‐small cell lung cancer[J]. Cancer Science, 2023, 114(11): 4343-4354.
Alectinib Hydrochloride是一种强效、选择性、可口服的ALK抑制剂，IC50值为1.9nM，Kd值为2.4nM[1]。Alectinib Hydrochloride可抑制L1196M突变的ALK，IC50值为1.56nM[2]。在过度表达ABCB1或ABCG2的细胞中，Alectinib Hydrochloride通过抑制转运蛋白的外排功能，增加阿霉素（DOX）和罗丹明123（Rho 123）等ABCB1/ABCG2底物的细胞内积累，并刺激ATP酶活性，同时与ABCB1或ABCG2的底物竞争[3]。Alectinib Hydrochloride已被广泛用于抑制具有ALK突变的肺癌细胞的生长[4]。
在体外，Alectinib Hydrochloride处理48小时显著抑制了H2228细胞和ABC-11细胞的增殖，IC50值分别为0.03µM和0.13µM[5]。使用30nM的Alectinib Hydrochloride处理48小时，显著抑制了PC12细胞中ALK介导的神经突生长[6]。使用10µM的Alectinib Hydrochloride处理48小时，诱导了U87MG细胞凋亡，抑制了STAT3的酪氨酸磷酸化，并激活了Janus激酶2（JAK2）的酪氨酸磷酸化[7]。
在体内，单次腹腔注射50mg/kg剂量的Alectinib Hydrochloride 24小时，显著减轻了缺血性卒中小鼠模型中的脑梗死和神经功能缺损，以及脑血管完整性的丧失和血脑屏障的损伤[8]。每日口服10mg/kg剂量的Alectinib Hydrochloride，持续4周，显著抑制了H3122细胞异种移植小鼠模型中的肿瘤生长，且未影响小鼠的体重[9]。