Discovery of YKS-34 , a Highly Selective PDE4B Inhibitor for the Treatment of Idiopathic Pulmonary Fibrosis

Abstract Idiopathic pulmonary fibrosis (IPF) remains a progressive and fatal lung disease with a substantial unmet need for safe and effective therapies. Highly selective inhibition of phosphodiesterase 4B (PDE4B) represents a promising therapeutic strategy for IPF while avoiding nausea and vomiting associated with PDE4D inhibition. However, achieving pronounced subtype selectivity remains particularly challenging; notably, the only approved PDE4B-preferential inhibitor, nerandomilast, exhibits only approximately 9-fold selectivity for PDE4B over PDE4D. Herein, we report the identification of YKS-34, a potent PDE4B inhibitor (IC50 = 1.71 nM) exhibiting >1000-fold selectivity over PDE4A, PDE4C, and PDE4D. YKS-34 effectively suppressed TGF-β-induced fibroblast activation and LPS-induced TNF-α release in vitro. In vivo, YKS-34 showed favorable pharmacokinetic properties, lung tissue accumulation, and reduced emetic potential at tested conditions while dose-dependently improving pulmonary dysfunction and fibrotic remodeling in a bleomycin-induced IPF mouse model. Consequently, YKS-34 emerges as a highly promising, next-generation candidate for the treatment of IPF.