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Updated: Jun 18, 2025

Utilizing Functional Genomics Screening to Identify Potentially Novel Drug Targets in Cancer Cell Spheroid Cultures
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Utilizing Functional Genomics Screening to Identify Potentially Novel Drug Targets in Cancer Cell Spheroid Cultures

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A selective S-acyltransferase inhibitor suppresses tumor growth

Jia-Ying Lee, Sebastian Dilones, Timothe Maujean

    Biorxiv : the Preprint Server for Biology
    |August 2, 2024
    PubMed

    Insights

    Researchers identified a novel inhibitor, SD-066-4, targeting ZDHHC20 to block lung tumor growth. This S-acylation inhibitor shows promise for treating Kras-mutant lung cancers and improving patient survival.

    Area of Science:

    • Biochemistry and Molecular Biology
    • Oncology
    • Drug Discovery

    Background:

    • S-acyltransferases are crucial for physiological processes, including oncogenic signaling.
    • The lack of specific S-acylation inhibitors hinders therapeutic development for diseases.
    • Targeting S-acyltransferases offers potential benefits for human diseases, but remains largely unexplored.

    Purpose of the Study:

    • To identify and characterize a novel, orally bioavailable inhibitor of S-acyltransferases.
    • To investigate the therapeutic potential of inhibiting ZDHHC20 in Kras-mutant lung cancer.
    • To explore the clinical relevance of ZDHHC20 and ZDHHC14 in lung cancer patient outcomes.

    Main Methods:

    • Identification of an orally bioavailable acyltransferase inhibitor, SD-066-4.
    • Characterization of SD-066-4's isoform selectivity through alanine residue interaction.
    • Assessment of SD-066-4's effect on EGFR S-acylation in Kras mutant cells.
    • Evaluation of SD-066-4's efficacy in blocking Kras mutant lung tumor growth and survival in preclinical models.
    • Analysis of lung cancer patient data for correlations between ZDHHC20/ZDHHC14 deletions, Kras alterations, and survival benefit.

    Main Results:

    • SD-066-4 was identified as an orally bioavailable inhibitor of the acyltransferase ZDHHC20.
    • A specific alanine residue was found to confer isoform selectivity to SD-066-4.
    • SD-066-4 effectively reduced EGFR S-acylation in Kras mutant cells.
    • The inhibitor blocked Kras mutant lung tumor growth and extended overall survival.
    • Lung cancer patients with ZDHHC20/ZDHHC14 deletions and Kras alterations showed a significant survival benefit.

    Conclusions:

    • SD-066-4 is a potent and selective inhibitor of ZDHHC20 with demonstrated efficacy against Kras-mutant lung tumors.
    • Pharmacological inhibition of ZDHHC20 represents a promising therapeutic strategy for Kras-mutant lung cancer.
    • The findings highlight the translational importance of ZDHHC20 and ZDHHC14 in lung cancer treatment and patient stratification.

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