NIC3

NIC3 is a small-molecule inhibitor and protein degrader that targets Nucleus accumbens-associated protein 1 (NAC1), a BTB/POZ domain-containing transcriptional repressor. NAC1 is frequently overexpressed in several cancers, including uterine corpus endometrial carcinoma (UCEC), where it promotes tumor growth, metastasis, and resistance to chemotherapy by regulating the NR2F6-NACC1-NOTCH3 axis and PD-L1 expression. NIC3 functions by binding to NAC1, preventing its essential homodimerization and subsequently triggering its proteasomal degradation. This disruption of NAC1-mediated signaling leads to the downregulation of downstream effectors such as NOTCH3 and PD-L1, thereby inhibiting tumor cell proliferation and potentially overcoming therapy resistance. Developed by researchers at the University of South Florida, NIC3 is being investigated as a novel therapeutic strategy for high-grade or treatment-resistant endometrial cancer.