at-13387 and resorcinol

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 ALK

Topics: Anaplastic Lymphoma Kinase; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Drug Design; Drug Screening Assays, Antitumor; HSP90 Heat-Shock Proteins; Humans; Molecular Docking Simulation; Molecular Structure; Protein Kinase Inhibitors; Pyrimidines; Receptor Protein-Tyrosine Kinases; Resorcinols; Structure-Activity Relationship

The synthesis of C-5-substituted resorcinol amide AT13387, a known Hsp90 inhibitor currently in clinical trials, is reported without the use of phenolic protection in an overall yield of 13.4%. Biomimetic aromatization and Suzuki-Miyaura cross coupling approach were employed to synthesize the resorcinol and iso-indoline units, respectively, which were efficiently coupled using Grignard-mediated amidation.

Topics: Amides; Benzamides; Chemistry Techniques, Synthetic; Drug Design; HSP90 Heat-Shock Proteins; Isoindoles; Resorcinols