Design, synthesis and pharmacological evaluation of ALK and Hsp90 dual inhibitors bearing resorcinol and 2,4-diaminopyrimidine motifs

• Published in: European journal of medicinal chemistry 2018-05, Vol.152, p.76-86
• Main Authors: Geng, Kaijun, Liu, Hongchun, Song, Zilan, Zhang, Chi, Zhang, Minmin, Yang, Hong, Cao, Jingchen, Geng, Meiyu, Shen, Aijun, Zhang, Ao
• Format: Article
• Language: English
• Subjects: Antiproliferative activity; Drug resistance; Dual inhibitor; Heat shock protein 90 (Hsp90); Tyrosine kinase ALK
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2018.04.019

Rather than by directly focusing on the ever-changing ALK mutants, here we report an alternative strategy to overcome the drug resistance caused by treatment of ALK inhibitors by developing ALK and Hsp90 dual targeting inhibitors. Since Hsp90 is a molecular chaperone that regulates the maturation, activation and stability of numerous “client proteins” including ALK, dual targeting ALK and Hsp90 may bring more benefits and efficacy against drug resistance of ALK inhibitors. By using our previously developed ALK inhibitor 6 and the clinical Hsp90 inhibitors AUY922 or AT13387 as the templates, we developed several series of resorcinol tethered 2,4-diaminopyrimidines as ALK/Hsp90 dual inhibitors bearing various linkers at different linking sites. Compound 10h and 10j showed high potency against ALK (17.3 vs 9.8 nM) and Hsp90α (100 vs 40 nM). They also have high potency against ALK resistant mutants, especially the gatekeeper mutation ALKL1196M. Both compounds showed strong antiproliferative activity against the ALK-addictive H3122 cells (11 vs 13 nM). The dual functioning mechanism is further confirmed by their down-regulation of the Hsp90 clients ALK and AKT, and up-regulation of the chaperone protein Hsp70 in H3122 cells. [Display omitted] •Hsp90 is a molecular chaperone that regulates kinase stability including ALK.•Through hybridizing strategy, ALK/Hsp90 dual inhibitors were identified.•10h and 10j showed potent inhibitory activity against ALKL1196M mutant.•10h and 10j exerted excellent antiproliferative effects against H3122 cells.•Both 10h and 10j significantly down-regulated the levels of ALK.