PLM-103：一种双机制 YES1/YAP 通路抑制剂，展现广谱抗肿瘤疗效及免疫肿瘤学协同作用

The Hippo-YAP pathway is a key regulator of tumor progression, metastasis, and immune evasion. Aberrant activation of YAP promotes epithelial-mesenchymal transition (EMT), suppresses immune cell infiltration, and contributes to poor immune responsiveness in various cancers. YES1, a Src family kinase, functions as a critical upstream activator of YAP nuclear signaling, and its oncogenic amplification has been reported in multiple YAP-driven malignancies. Therefore, pharmacologic inhibition of YES1 represents a promising approach to suppress YAP (Yes-Associated Protein) activity and identify new therapeutic strategies targeting YAP-dependent tumors. PLM-103 is a novel small-molecule inhibitor that potently inhibits YES1 kinase and concurrently suppresses TEAD-mediated transcription, leading to robust inactivation of YAP signaling. Through this dual mechanism, PLM-103 achieves TEAD inhibition comparable to classical TEAD inhibitors but exhibits superior suppression of cell proliferation and downstream oncogenic signaling, translating into potent in vivo antitumor efficacy. Unlike conventional TEAD inhibitors whose activity is largely restricted to mesothelioma, PLM-103 demonstrates broad spectrum antitumor activity across YAP-driven cancers including esophageal squamous cell carcinoma (ESCC), renal cell carcinoma (RCC), pancreatic ductal adenocarcinoma (PDAC), and mesothelioma. In the KYSE70 ESCC xenograft model, PLM-103 monotherapy exhibited a remarkable antitumor effect, achieving complete tumor regression (CR) in 4 out of 7 mice. In this in vivo model, PLM-103 treatment significantly reduced the expression of CYR61 and CTGF, YAP target genes, confirming effective suppression of YAP transcriptional activity in tumors. Mouse PK study demonstrated that PLM-103 is orally available and provides sufficient systemic exposure to exert its pharmacologic effects. Additional ADME and safety profiling, including metabolic stability, plasma protein binding, and hERG assay, confirmed that PLM-103 possesses favorable drug-like properties suitable for further development. When combined with the immune checkpoint inhibitor anti-PD-1 antibody, PLM-103 exhibited remarkable synergistic efficacy characterized by enhanced infiltration of CD8⁺ effector T cells and reduced regulatory T (Treg) cells within the tumor microenvironment. The combination of PLM-103 with anti-PD-1 therapy resulted in durable complete responses, underscoring the potent immunomodulatory and immune-potentiating capacity of PLM-103. Collectively, these findings establish PLM-103 as a highly promising next-generation anticancer agent that integrates targeted YES1/YAP pathway inhibition with robust immunomodulatory activity, providing dual and complementary mechanisms capable of addressing a broad range of YAP-driven malignancies.