ARTS-876（一种靶向KEAP1/NFE2L2突变型NSCLC的AKR1C3激活型前药）的临床前评估

The Kelch-like ECH-associated protein 1 (KEAP1)/nuclear factor erythroid 2-related factor 2 (NRF2, encoded by NFE2L2) pathway is a master regulator of cellular redox homeostasis. Somatic KEAP1 or NFE2L2 mutations occur in approximately 20% of non-small cell lung cancer (NSCLC) cases, representing a significant patient cohort. These mutations result in constitutive NRF2 activation, driving tumorigenesis, metastatic potential, and broad resistance to chemotherapy, targeted therapy, and immunotherapy. Utilizing a commercially available repurposing library and a proprietary compound collection, we conducted a high-throughput phenotypic screen to identify candidates that selectively inhibit KEAP1-mutant NSCLC cells while sparing KEAP1/NFE2L2-wild-type cells. Validation data from an expanded panel of NSCLC cell lines confirmed the selectivity of the top hits for KEAP1/NFE2L2-mutant cells. Mechanistic characterization revealed that the lead candidate is a specific substrate of aldo-keto reductase 1C3 (AKR1C3), an enzyme whose overexpression is a key downstream consequence of sustained NRF2 signaling. This discovery offers an alternative therapeutic approach for KEAP1/NRF2 mutant tumors, in which direct pharmacologic inhibition of NRF2 has remained challenging because, as a transcription factor, it generally lacks well-defined small molecule binding pockets. Subsequent medicinal chemistry optimization yielded ARTS-876, a novel AKR1C3-activated prodrug engineered to target KEAP1/NFE2L2-mutant tumors, including NSCLC. In AKR1C3-high tumor cells, ARTS-876 is selectively reduced to its active metabolite, ALRN-1018, a DNA-alkylating agent that induces DNA damage and cell death. In vitro, ARTS-876 selectively inhibits the proliferation of KEAP1/NFE2L2-mutant, AKR1C3-high NSCLC cell lines and induces robust, dose-dependent activation of canonical DNA damage response markers. Conversely, ARTS-876 displays minimal activity in wild-type H1299 cells and normal human PBMCs or hepatocytes, supporting a wide therapeutic index. In vivo, ARTS-876 demonstrates potent antitumor efficacy in multiple KEAP1/NFE2L2-mutant NSCLC CDX models, a syngeneic mouse model engineered to overexpress human AKR1C3, and KEAP1/NFE2L2-mutant PDX models. In contrast, minimal inhibition was observed in wild-type CDX and PDX models. Furthermore, ARTS-876 enhances antitumor immunity by increasing intratumoral CD3+ and CD8+ T-cell infiltration as monotherapy and shows combinatorial efficacy with anti-PD-1 antibodies without additive toxicity, providing a rationale for combination with immune checkpoint inhibitors A first-in-human Phase 1a/1b trial in advanced NSCLC harboring KEAP1/NFE2L2 alterations is currently ongoing in China.