Identification and anti-tumor evaluation of 3-acyl-indol-based 2,4-diarylaminopyrimidine analogues as potent ALK inhibitors capable of overcoming drug-resistant mutants

• Published in: European journal of medicinal chemistry 2022-08, Vol.238, p.114493-114493, Article 114493
• Main Authors: Guo, Ming, Wang, Hao, Yang, Jing, Wang, Xinyu, Zhang, Jiahao, Liu, Shuyu, Wei, Shangfei, Jiang, Nan, Zhai, Xin
• Format: Article
• Language: English
• Subjects: 2,4-Diarylaminopyrimidine; ALK; Antitumor evaluation; Design & synthesis; G1202R mutant
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2022.114493

A series of novel 2,4-diarylaminopyrimidine analogues (G-1∼G-8 and I-1∼I-24) were rationally designed by incorporating 2-alkyl-3-acyl-1H-indol fragment to interact with the hydrophobic region of the intractable ALKG1202R mutant. Wherein, compound I-24 bearing a 2-methyl-3-dimethylformamido-1H-indol moiety was identified as the most promising ALK inhibitor with IC50 values below 4 nM against ALKWT, ALKL1196M and ALKG1202R, accompanied by concrete down-regulation of phospho-ALK and its relative downstream signaling. Subsequently, I-24 displayed significant anti-proliferative activity in the nanomolar range towards ALK-positive cell lines including a panel of Ba/F3 cells harboring mutational ALK. Dramatically, the involvement of I-24 decreased colony formation and migration tendency on H2228 cells. Meanwhile, flow cytometry analysis indicated that I-24 could induce cell apoptosis and achieve cell cycle arrest in G1 phase. Notably, oral administration of I-24 at 50 mg/kg regressed tumor in the H2228 xenograft model with tumor growth inhibition value of 93.5%. Collectively, I-24 with favorable PK profile was supposed to further investigation as potent ALK inhibitor to circumvent clinical drug resistance. [Display omitted] •3-acyl-indol-based 2,4-diarylaminopyrimidine analogues were designed and synthesized.•I-24 was identified as a potent ALK inhibitor with anti-mutation effects.•I-24 down-regulated the phosphorylation of ALK and its downstream proteins.•I-24 exhibited good liver microsomal stability with rational PK profiles.•I-24 significantly suppressed the tumor growth in H2228 xenograft mouse model.