NP1192 is a potent and selective PROTAC NAT10 degrader that reduces NAT10 protein expression in cancer cells and inhibits ac4C modification. It disrupts the NAT10/HIF-1α/PD-L1 axis, leading to dual suppression of hypoxia-driven glycolysis and immunosuppression, demonstrating significant antitumor efficacy both in vitro and in vivo, and producing synergistic effects when combined with anti-PD-L1 treatment. NP1192 is applicable for research in ovarian cancer, cervical cancer, and glioblastoma.

NP1192 induces the degradation of NAT10 in SiHa (human) and U14 (mouse) cervical cancer cell lines in a dose- and time-dependent manner at concentrations ranging from 0-20 μM over 24-48 hours. This process occurs through the ubiquitin-proteasome system (UPS) rather than the lysosomal pathway. NP1192, over 36 hours, inhibits the growth of cervical cancer (SiHa) cells with an IC50 value of 7.814 μM (76.2 μM in resistant cells) and exhibits dose-dependent efficacy in organoids of ovarian cancer (OV), cervical cancer (CESC), and glioblastoma (GBM) with IC50 values of 9.947, 3.048, and 13.76 μM, respectively. At 20 μM for 0-72 hours and up to 2 weeks, NP1192 significantly reduces the viability of cervical cells, induces cell cycle arrest, and inhibits their invasion and colony formation abilities. When applied at 0.195-50 μM for 1-8 days, NP1192 markedly reduces the size and number of tumor model organoids (ovarian cancer, cervical cancer, and glioblastoma) without affecting corresponding normal organoids, indicating minimal cytotoxicity to non-malignant tissues. At 20 μM for 36 hours, NP1192 degrades NAT10 and subsequently impairs HIF-1α expression, reprogramming the hypoxic tumor microenvironment and metabolism of cervical cancer cells, characterized by reduced glucose uptake and lactate production along with increased ATP levels, thereby disrupting glycolysis.

NP1192 (25 mg/kg, administered via intraperitoneal injection every two days for one week) works synergistically with an anti-PD-L1 antibody to inhibit tumor growth, suppress glycolysis, and enhance CD8+ T effector cell immune function in the U14-luc xenograft mouse model.