Discovery of YKS-34 , a Highly Selective PDE4B Inhibitor for the Treatment of Idiopathic Pulmonary Fibrosis
Tongfei Jing, Chang Fu, Runzhi Zhang, Zhuo Shi, Zhiyi Wu, Ruibo Lin, Weibin Zeng, Peiyu Zhang, Shiyang Shen, Zhenghui Kang, Yushe YangAbstract
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.