**Background**
Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase that can undergo rearrangement, leading to the expression of EML4-ALK fusion proteins. This oncogenic driver is frequently found in a subset of non-small-cell lung cancers (NSCLC), where it promotes tumor cell proliferation, survival, and metastasis. Due to its critical role in driving malignancy, ALK has become a primary therapeutic target for the development of precision medicines in lung cancer. However, the emergence of resistant mutations, such as the gatekeeper mutation, often limits the long-term efficacy of first-generation inhibitors. Furthermore, the ability of a drug to penetrate the blood-brain barrier is essential for treating CNS metastases, which are common in ALK-positive patients. In this context, we will introduce a potent and selective ALK inhibitor – Alectinib.
**Definition**
Alectinib is a potent, selective, and orally available ALK inhibitor with an IC50 of 1.9 nM and a Kd value of 2.4 nM in an ATP-competitive manner. According to the Alectinib description, it also effectively inhibits the resistant mutants ALK F1174L and ALK R1275Q with IC50 values of 1 nM and 3.5 nM, respectively.
**In Vitro and In Vivo Studies**
The Alectinib biological activity has been extensively validated across various models. In Alectinib in vitro studies, treatment with concentrations ranging from 0 to 1000 nM for 2 hours in NCI-H2228 cells expressing EML4-ALK prevented the autophosphorylation of ALK and substantially suppressed the phosphorylation of STAT3 and AKT. Additionally, treatment with 0-1000 nM Alectinib for 5 days reduced cell activity in a dose-dependent manner in HCC827, A549, and NCIH522 cell lines.
Regarding Alectinib In Vivo efficacy, SCID or nude mice bearing NCI-H2228 cells were administered Alectinib orally once daily for 11 days at doses ranging from 0.2 to 20 mg/kg. This treatment resulted in dose-dependent tumor growth inhibition, with an EC50 of 0.46 mg/kg, and led to tumor regression. Notably, no significant differences in body weight or gross signs of toxicity were observed at any dose level. Furthermore, Alectinib demonstrates effective central nervous system (CNS) penetration, making it a valuable tool for Alectinib Cancer research. In conclusion, Alectinib is a highly potent and selective ALK inhibitor capable of overcoming resistant mutations and penetrating the CNS.
Keywords
Alectinib, 1256589-74-8, CH5424802, RO5424802, AF-802, CH 5424802, CH-5424802, RO 5424802, RO-5424802, AF802, AF 802, Anaplastic lymphoma kinase (ALK), Anaplastic lymphoma kinase, ALK tyrosine kinase receptor, CD246
References
[1] Sakamoto H, et al. CH5424802, a selective ALK inhibitor capable of blocking the resistant gatekeeper mutant. Cancer Cell. 2011, 19(5), 679-690.
[2] Gadgeel S, et al. Alectinib versus crizotinib in treatment-naive anaplastic lymphoma kinase-positive (ALK+) non-small-cell lung cancer: CNS efficacy results from the ALEX study. Ann Oncol. 2018 Nov 1;29(11):2214-2222.