The structure-based optimization of 3-substituted indolin-2-one derivatives as potent and isoform-selective c-Jun N-terminal kinase 3 (JNK3) inhibitors and biological evaluation

An indolin-2-(4-thiazolidinone) scaffold was previously shown to be a novel chemotype for JNK3 inhibition. However, more in vivo applications were limited due to the unconfirmed configuration and poor physicochemical properties. Here, the indolin-2-(4-thiazolidinone) scaffold validated the absolute configuration; substituents on the scaffold were optimized. Extensive structure activity relationship (SAR) studies were performed using kinase activity assays, thus leading to potent and highly selective JNK3 inhibitors with neuroprotective activity and good oral bioavailability. One lead compound, A53, was a potent and selective JNK3 inhibitor (IC50 = 78 nM) that had significant inhibition (>80% at 1 μM) to only JNK3 in a 398-kinase panel. A53 had low inhibition against JNK3 and high stability (t1/2(α) = 0.98 h, t1/2(β) = 2.74 h) during oral administration. A modeling study of A53 in human JNK3 showed that the indolin-2-(4-thiazolidinone)-based JNK3 inhibitor with a 5-position-substituted hydrophilic group offered improved kinase inhibition. [Display omitted] •SAR study of a series of indolin-2-(4-thiazolidinone)-based JNK3 inhibitors was performed.•The synthetic method and final configuration of the indolin-2-(4-thiazolidinone) scaffolds was studied in detail.•Compound A53 displayed highly potent JNK3 inhibitory ability and excellent kinome-wide selectivity to JNK3 among the 398 screened kinases.•Compound A53 exhibited low cytotoxicity and robust neuroprotective activity against Aβ25−35.•Compound A53 showed higher Cmax and AUC0-t than J30-8 by oral administration.