1356962-20-3

AZD3463, is a novel ALK/IGF1R dual Inhibitor, having the ability of overcoming multiple mechanisms of acquired resistance to Crizotinib (C785000).

ChEBI: AZD3463 is a member of the class of indoles that is 1H-indole substituted by a 2-[4-(4-aminopiperidin-1-yl)-2-methoxyanilino]-5-chloropyrimidin-4-yl group at position 3. It is an orally bioavailable dual inhibitor of ALK and IGF1R with Ki value of 0.75 nM for ALK. It has a role as an apoptosis inducer, an antineoplastic agent, an EC 2.7.10.1 (receptor protein-tyrosine kinase) inhibitor and an autophagy inducer. It is a member of indoles, an aminopiperidine, a monomethoxybenzene, an aminopyrimidine, a secondary amino compound, a tertiary amino compound and an organochlorine compound.

azd3463 is a novel orally bioavailable alk/igf1r inhibitor with ki value of 0.75 nm. alk expression is largely restricted to neurons and upregulated in neuroblastoma. activated alk has been shown to promote cell survival and growth. high alk expression or mutations in the alk gene correlates with adverse outcomes in neuroblastoma. therefore, alk receptor tyrosine kinase is an important therapeutic target for drug development against neuroblastoma [1].

azd3463 (5, 10, 20, and 50 μm) effectively inhibited the proliferation of neuroblastoma cell lines with wild type alk (wt) and alk activating mutations (f1174l and d1091n) via targeting the alk-mediated pi3k/akt/mtor pathway and ultimately induced apoptosis and autophagy in vitro. moreover, azd3463 (1 μm) significantly enhanced the cytotoxic effects of doxorubicin (1 μm) on neuroblastoma cells [1]. azd3463 simultaneously inhibited stat3 and akt to augment the cytotoxic effects of temozolomide and further reduce cell growth [2].

This novel, orally bioavailable ALK inhibitor (FW = 448.95 g/mol; CAS 1356962-20-3; Solubility: 24 mg/mL DMSO; <1 mg/mL H2O), also named N-[4- (4-amino-1-piperidinyl) -2-methoxyphenyl]-5-chloro-4- (1H-indol-3- yl) -2-pyrimidinamine, inhibits Anaplastic Lymphoma Kinase (ALK) with a Ki of 0.75 nM and overcomes multiple mechanisms of acquired crizotinib resistance. AZD3463 inhibits ALK in cells as demonstrated by its ability to decrease ALK autophosphorylation in tumor cell lines containing ALK fusions, including DEL (ALCL NPM-ALK), H3122 (NSCLC EML4-ALK) and H2228 (NSCLC EML4-ALK) mutant forms. Inhibition of ALK is associated with perturbations in downstream signaling including ERK, AKT and STAT3 pathways leading to preferential inhibition of proliferation in the ALK fusion containing cell lines in vitro. AZD3463 also demonstrates the ability to dose dependently inhibit pALK in xenograft tumors in vivo resulting in stasis or regression. Other Target (s) : AZD3463 also inhibits additional receptor tyrosine kinases including insulin growth factor receptor (IGF1R) with equivalent potency.

azd3463 (15 mg/kg, i.p. injection) showed significant therapeutic efficacy on the growth of the neuroblastoma tumors with wt and f1174l oncogenic mutant alk in orthotopic xenograft mouse models [1].

alk, igf1r

0.75 nm(ki)

Store at -20°C

1. wang y, wang l, guan s, cao w, wang h, chen z, et al. novel alk inhibitor azd3463 inhibits neuroblastoma growth by overcoming crizotinib resistance and inducing apoptosis. sci rep. 2016;6:19423. 2. sampson vb, vetter ns, kamara df, collier ab, gresh rc, kolb ea. vorinostat enhances cytotoxicity of sn-38 and temozolomide in ewing sarcoma cells and activates stat3/akt/mapk pathways. plos one. 2015;10(11):e0142704.