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Identification of an SFRP1 inhibitor as a novel therapeutic strategy for cancers using dry-wet combined drug discovery strategy
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Abstract
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 promising therapeutic target for advanced malignancies. In this study, a 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 confirmed the specific binding of compound
L1
to SFRP1 with a dissociation constant (KD) of 79.1 nM. Furthermore, molecular docking and molecular dynamics (MD) simulation elucidated the interaction between compound
L1
and SFRP1 at the molecular level and in physiological conditions.
Springer Science and Business Media LLC
Title: Identification of an SFRP1 inhibitor as a novel therapeutic strategy for cancers using dry-wet combined drug discovery strategy
Description:
Abstract
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 promising therapeutic target for advanced malignancies.
In this study, a 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 confirmed the specific binding of compound
L1
to SFRP1 with a dissociation constant (KD) of 79.
1 nM.
Furthermore, molecular docking and molecular dynamics (MD) simulation elucidated the interaction between compound
L1
and SFRP1 at the molecular level and in physiological conditions.
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