1097917-15-1

ASP3026 is an ATP-competitive, second-generation ALK inhibitor (IC₅₀ = 3.5 nM) that also inhibits ROS (IC₅₀ = 8.9 nM) and ACK (IC₅₀ = 5.8 nM). It inhibits neuroblastoma-activating ALK mutants F1174L (IC₅₀ = 10 nM) and R1275Q (IC₅₀ = 5.4 nM) and demonstrates antitumor activity in xenograft mouse models. ASP3026 has been shown to overcome crizotinib resistance in non-small cell lung cancer, and is currently being evaluated in clinical trials of patients with ALK-positive solid tumors.

ASP3026 is a novel and selective anaplastic lymphoma kinase (ALK) inhibitor that shows potent anti-tumor activities. ASP3026 also shows potential efficacy for non-small cell lung cancer (NSCLC) and is expected to improve the therapeutic outcomes of patients with cancer with ALK abnormality. Potent ALK inhibitor.

ChEBI: ASP-3026 is a member of the class of diamino-1,3,5-triazines that is 1,3,5-triazine-2,4-diamine in which the amino groups at positions 2 and 4 are respectively carrying 2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl and 2-(propan-2-ylsulfonyl)phenyl substituents. It is a potent inhibitor of anaplastic lymphoma kinase (ALK), Ack and ROS1 activity (IC50 values are 3.5, 5.8 and 8.9 nM respectively) and exhibits anti-cancer properties. It has a role as an antineoplastic agent, an apoptosis inducer, an EC 2.7.10.1 (receptor protein-tyrosine kinase) inhibitor, an antimalarial and an EC 6.1.1.6 (lysine--tRNA ligase) inhibitor. It is a secondary amino compound, a monomethoxybenzene, a N-methylpiperazine, an aromatic amine, a diamino-1,3,5-triazine, a member of piperidines and a sulfone.

Alternative to Step 7, Method 2 (Example of using a reducing catalyst): Synthesis of N-{2-methoxy-4-[4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}-N'-[2-(propane-2-sulfonyl)phenyl]-1 ,3,5-triazine-2,4-diamine (compounds of formula (1)). 1-[3-Methoxy-4-({4-[2-(propane-2-sulfonyl)anilino]-1,3,5-triazin-2-yl}amino)phenyl]piperidin-4-one (5.0 g), tetrahydrofuran (30 mL), N-methylpiperazine (1.81 g), and 10% palladium-carbon (~50% wet product, 0.8 g) were mixed. The mixture was stirred at 40°C for 7 hours under a hydrogen atmosphere (2.4821 x 10^5 Pa). Upon completion of the reaction, the palladium carbon was removed by filtration and washed with tetrahydrofuran (10 mL). The combined filtrates were concentrated under reduced pressure. To the concentrated residue was added 2-butanone (9 mL) and the resulting mixture was stirred at 60°C for 30 minutes and then slowly cooled to 30°C. After addition of n-heptane (9 mL), the mixture was stirred at room temperature for 19 h. The precipitated crystals were collected by filtration. The crystals were washed with a mixture of 2-butanone (1 mL) and n-heptane (1 mL) and then dried under reduced pressure at 40 °C to afford the target product N-{2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}-N'-[2-(propane-2-sulfonyl)phenyl]-1,3,5-triazine-2,4-diamine (3.09 g, yield 88.0%). Nuclear magnetic resonance hydrogen spectroscopy (1H NMR) data: δ 1.31 (6H, d, J = 6.8Hz), 1.59-1.78 (2H, m), 1.90-2.01 (2H, m), 2.24-2.80 (11H, m), 2.30 (3H, s), 3.19-3.32 (1H, m), 3.65-3.75 (2H, m), 3.88 (3H, m). 3.88 (3H, s), 6.50-6.59 (2H, m), 7.18-7.30 (1H, m), 7.53-7.70 (2H, m), 7.88 (1H, dd, J = 1.5, 8.3Hz), 8.10 (1H, br), 8.37 (1H, br), 8.53 (1H, br), 9.29 (1H, s). Mass spectrum (ESI+): m/z 581.

This potent signal transduction inhibitor (FW = 580.74 g/mol; CAS 1097917-15-1; Solubility: 14 mg/mL DMSO; <1 mg/mL H2O), also known as N2-[2-methoxy-4-[4- (4-methyl-1-piperazinyl) -1-piperidinyl]phenyl]-N4- [2-[ (1-methylethyl) sulfonyl]phenyl]-1,3,5-triazine-2,4-diamine, targets ALK, the Activin receptor-Like Kinase activity of Transforming Growth Factor-b (TGF-b) receptors, with IC50 of 3.5 nM. ASP3026 inhibits ALK in an ATP-competitive manner with an inhibitory spectrum that differs from crizotinib, a dual ALK/MET inhibitor. In patients with non-small cell lung cancer, a therapeutic target is the EML4-ALK fusion protein, which is formed between echinoderm microtubule-associated protein like 4 and ALK as a consequence of the rearrangement of ALK and EML4 genes. In mice xenografted with EML4-ALK-expressing NCI-H2228 cells, orally administered ASP3026 is well absorbed in tumor tissues, reaching concentrations >10-fold higher than those in plasma, and induces tumor regression with a wide therapeutic margin between efficacious and toxic doses. In the same mouse model, ASP3026 enhances the antitumor activities of paclitaxel and pemetrexed without affecting body weight. ASP3026 also showed potent antitumor activities, including tumor shrinkage to a undetectable level, in hEML4-ALK transgenic mice and prolonged survival in mice with intrapleural NCI-H2228 xenografts. Finally, ASP3026 exhibiL1t1e9d6M potent antitumor activity against cells expressing EML4-ALK, a mutation conferring resistance to crizotinib.

ROS; ACK; Caspase-3; PARP1; IGF-1R; STAT3

Store at -20°C

[1] kuromitsu s, mori m, shimada i, et al. anti-tumor activity of asp3026, a novel and selective alk inhibitor of anaplastic lymphoma kinase (alk).annual meeting of the american association for cancer research (aacr), orlando, fl. 2011.
[2] mori m, ueno y, konagai s, et al. the selective anaplastic lymphoma receptor tyrosine kinase inhibitor asp3026 induces tumor regression and prolongs survival in non–small cell lung cancer model mice. molecular cancer therapeutics, 2014, 13(2): 329-340.
[3] george s k, vishwamitra d, manshouri r, et al. the alk inhibitor asp3026 eradicates npm-alk+ t-cell anaplastic large-cell lymphoma in vitro and in a systemic xenograft lymphoma model. oncotarget, 2014, 5(14): 5750-5763.