Identification of an SFRP1 inhibitor as a potential therapeutic strategy for cancers using dry-wet combined drug discovery strategy.

Secreted frizzled-related protein 1 (SFRP1) exerts a context-dependent dual role in cancer, and its epigenetic silencing drives pro-tumorigenic non-canonical Wnt activation, a potentially promising therapeutic target for advanced malignancies. In this study, a preliminarily validated 3D SFRP1 model was built by comprehensive computational approach. High-throughput virtual screening of a commercial compound library identified a common core scaffold, which was rationally design to synthesize lead compound. The target molecule was synthesized via organic synthetic approaches. Surface plasmon resonance (SPR) assays indicated concentration-dependent and specific binding of compound L1 to SFRP1 with a dissociation constant (KD) of 79.1 nM. Furthermore, molecular docking and molecular dynamics (MD) simulation provided insights into the interaction between compound L1 and SFRP1 at the molecular level and in simulated physiological conditions.