Description
AZD-3463 is a novel inhibitor of ALK with IC50 of 22 nM.
Storage
2 years -20 centigrade Powder; 2 weeks 4 centigrade in DMSO; 6 months -80 centigrade in DMSO.
Molecular Formula
C24H25ClN6O
Chemical Name
2-Pyrimidinamine, N-[4-(4-amino-1-piperidinyl)-2-methoxyphenyl]-5-chloro-4-(1H-indol-3-yl)-
Solubility
DMSO 24 mg/mL; Water <1 mg/mL; Ethanol <1 mg/mL
In vitro
AZD-3463 inhibits ALK with a Ki value of 0.75 nM. AZD-3463 retains good activity against a number of clinically relevant crizotinib-resistant mutations, including the gatekeeper mutantL1196M, where equivalent potency to wild-type ALK is observed in vitro in EML4-ALK-containing Ba/F3 cell lines. AZD3463 is potent in ALK-driven preclinical models and in a variety of crizotinib-resistant models. 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). 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 retains good activity against a number of clinically relevant crizotinib resistant mutations including the gatekeeper mutant L1196M where equivalent potency to wild type ALK is observed in vitro and in vivo in EML4-ALK containing BAF3 cell lines. To further assess the potential ability of AZD3463 to overcome additional resistance mechanisms, antiproliferative activity is assessed in multiple crizotinib resistant cell lines independently derived in vitro from H3122 cells as well as a patient derived crizotinib relapsed model. These resistant cell lines contain multiple resistance mechanisms including the L1196M gatekeeper and T115Ins mutations, ALK amplification and/or secondary drivers including EGFR and IGF1R. AZD3463 retains antiproliferative potency within 4 fold of parental H3122 cells for 10 out of 12 of these acquired resistance models in vitro.
In vivo
AZD-3463 dose-dependently inhibits pALK in tumor xenografts in vivo, resulting in stasis (H3122) or regression (DEL, H2228) in tumor volume. AZD-3463 obtains equivalent potency to mutantL1196M and wild-type ALK in vivo. AZD3463 also demonstrates the ability to dose dependently inhibit pALK in xenograft tumors in vivo resulting in stasis (H3122) or regression (DEL, H2228).
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