NRX-4972, a selective, oral, Aurora kinase A degrader, demonstrates increased efficacy in an SCLC tumor model, and greater in vitro synergy than an AURKA inhibitor

Aurora kinase A (AURKA) is frequently overexpressed in adult solid tumors, hematologic malignancies, and pediatric cancers. AURKA is a critical regulator of mitosis. Cancer cell lines particularly sensitive to AURKA loss include those derived from MYCN -amplified tumors (e.g., neuroblastoma) and from tumors with RB1 loss, such as neuroendocrine small cell cancers and CDK4/6-resistant breast cancers (Mou et al., 2021). Several AURKA inhibitors are effective in preclinical tumor models but have failed to translate into clinical efficacy. Recent studies have found that AURKA has kinase-independent scaffolding functions that are not effectively blocked through enzymatic inhibition (Otto, et al, Cancer Cell, 2009; Buchel, et al., Cell Reports, 2017). To address the limitations of inhibitors, we developed NRX-4972, a CNS-penetrant, orally bioavailable and highly selective degrader of AURKA designed to remove both enzymatic and scaffolding functions. NRX-4972 has a superior PK/PD profile compared with an AURKA inhibitor and more effectively induces DNA damage, apoptosis, and G2/M arrest. Previously, we demonstrated that once-daily oral administration of NRX-4972 provides robust efficacy in the H82 mouse tumor model of SCLC, while an AURKA inhibitor is ineffective (Tian et al.; AACR; Cancer Res 2025;85(8_Suppl_1): Abstract 6379). Here, we demonstrate that NRX-4972 achieves superior efficacy in the same tumor model when administered twice-daily (BID). After over two months of treatment with NRX-4972, 60% of mice survived to the end of the study. In contrast, none of the mice treated BID with the AURKA inhibitors alisertib or LY3295668 survived to the end of the study. To evaluate the benefit of AURKA degradation over inhibition in the combination setting, we performed an in vitro synergy screen across SCLC, NSCLC, and TNBC cancer cell lines. NRX-4972 and LY3295668 were compared in combination with a range of chemotherapeutics and targeted agents, and cell viability was evaluated for synergy using the Bliss independence model. The highest synergy scores were found in combination with NRX-4972, and more combinations with NRX-4972 resulted in synergy than with LY3295668. These data suggest that eliminating the kinase and scaffolding functions through degradation of AURKA increases the vulnerability of cancer cells to combination therapy. Collectively, NRX-4972's superior preclinical profile highlights the potential of AURKA degraders to overcome the limitations of AURKA inhibitors and achieve meaningful therapeutic benefit.