Ligand-Based Design of Lyn-Selective Type II Kinase Inhibitors by Rational Tail Modification of Imatinib

Lyn is a tyrosine kinase that plays critical roles in immune signaling and neurodegenerative diseases but is difficult to target selectively because of high homology within the Src-family of kinases. Here, we report ligand-based optimization of the type II inhibitor imatinib through systematic tail modification to enhance Lyn potency and selectivity. This approach yielded potent inhibitors, including compound 22 with low-nanomolar Lyn inhibition and compound 27 with 500-fold selectivity over Hck. Compound 22 showed a limited off-target kinase profile under low-ATP conditions that was further narrowed at 1 mM ATP while retaining submicromolar Lyn inhibition. Complementary 3D-QSAR and Markov state modeling linked tail-region steric features to ligand-dependent activation-loop conformational ensembles. In human microglia, 22 suppressed Aβ-induced Lyn autophosphorylation and increased CD163 high CLEC7A high DAM-like and Aβ-positive DAM-like populations. These findings establish compound 22 as a novel molecular probe for interrogating Lyn catalytic function across diverse disease-relevant contexts.