Discovery of a small-molecule NDR1 agonist for prostate cancer therapy

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Prostate cancer (PCa) is a leading cause of cancer death in men, often progressing to lethal castration-resistant prostate cancer (CRPC) after androgen deprivation therapy (ADT).
• Nuclear Dbf2-related kinase 1 (NDR1) is a kinase involved in tumorigenesis and metastasis; its reduced expression correlates with poor prognosis in PCa.
• There is an urgent need for novel therapeutic targets and drugs for advanced PCa.

Purpose of the Study:

• To develop and characterize a novel small-molecule agonist, aNDR1, targeting NDR1 for prostate cancer therapy.
• To evaluate the drug-like properties and antitumor efficacy of aNDR1 in preclinical models of PCa.

Main Methods:

• Characterization of aNDR1 for its specific binding to NDR1, and its effects on NDR1 expression, activity, and phosphorylation.
• Assessment of aNDR1's drug-like properties including stability, cell permeability, and PCa cell-specific toxicity.
• Evaluation of aNDR1's antitumor activity in vitro (proliferation, migration, apoptosis) and in vivo (subcutaneous tumors, lung metastasis).

Main Results:

• aNDR1 specifically binds to NDR1, potently promoting its expression, enzymatic activity, and phosphorylation.
• aNDR1 demonstrates favorable drug-like properties, including stability, cell permeability, and selective inhibition of PCa cells without affecting normal prostate cells.
• aNDR1 significantly inhibited PCa cell proliferation and migration, induced apoptosis in vitro, and reduced tumor growth and lung metastasis in vivo with no observed toxicity.

Conclusions:

• aNDR1 is a potent small-molecule agonist of NDR1 with significant preclinical antitumor activity against prostate cancer.
• aNDR1 exhibits desirable drug-like properties and selective toxicity towards cancer cells, making it a promising lead compound for PCa clinical therapy.