Effective Targeting of NAC1 Dimerization by a Small-Molecule Inhibitor and Application to Cancer Combination Therapy

[Speaker] Yi Zhang:1
[Co-author] Xiao-Hui Wang:1, Hong-Han Zhang:1, Cheng Ji:1, Ling-Chuan Guo:1, Jin-Ming Yang:2
1:Soochow University, China, 2:Penn State College of Medicine, Department of Pharmacology and The Penn State Cancer Institute, USA

Nucleus accumbens-associated protein-1 (NAC1), a nuclear factor of the BTB/POZ gene family, plays important roles in various biological processes such as maintenance of stem cell pluripotency and pathogenesis of human cancer, therefore NAC1 maybe represented as one potential attractive target for intervention. Herein, we identified core unit consisting of Met17 and Leu85 in the structured N-terminal (1-130) domain which is critical for NAC1 dimerization and stability. Through a combination of computational analysis of the dimerization interface and high-throughput screening (HTS) approach, we reported one compound (NIC3) selectively bound to the conserved Leu85 of NAC1 and inhibited NAC1 dimerization, leading to proteasome-mediated degradation of NAC1 protein. Remarkably, we demonstrated NIC3 exhibited strong combination therapy efficacy, reinforced the antitumor efficacy of cisplatin or adriamycin in vitro and in vivo. Our study first offers a preclinical validation of NAC1 dimerization as a new target for cancer therapeutic intervention, and highlights the potential for use in the development of chemotherapy in human cancer that depends on NAC1.

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