Identification And Antitumor Effect Of A Small Molecule Compound NIC19 Targeting The NAC1 Homodimerization

Excessive activation of oncogenic transcription factors is closely associated with malignant phenotypes,including proliferation,invasion,metastasis and therapeutic resistance,which attract a great deal of interests in this regard.NACI,a new putative oncogenic transcription factor uncovered by us and our collaborators,plays important roles in pathogenesis of human cancer.To our knowledge,there are no reports of inhibitor design against this protein.In this study,we identified core unit consisting of Met7 and Leu90 in the structured N-terminal(1-130)domain which is critical for NAC1 dimerization and stability.Important binding site(Leu90)mutant could destroy the formation of NAC1 dimer and significantly reduce stability.On the basis of these findings,through a combination of computational analysis of the dimerization interface and high-throughput screening(HTS)approach,we found a small molecular lead compound NIC 19,which has reasonable interaction with NAC1 protein,good inhibitory activity and demonstratedNIC19 could ubiquitinate and degrade NAC1 through inhibiting NAC1 homodimerization.We further explored the potent compound NIC 19 as anovel application for cancer combination therapy.