Abstract 6379: Identification of selective, orally bioavailable aurora A degraders for treatment of pediatric and adult cancers
Authors: Hua Tian, Eric Wegrzyniak, Ya-Wen Lu, Jeffrey T. Mihalic, Ryan Rountree, Tina Acholla, Bikash Adhikari, Karthik Arumugam, Paul Auger, Graham Carlson, Robert Cass, Coleen E. Casey, Abhinav Chaterjee, Lorenz Eing, James Iuliano, Adrienne Le, Yifan Li, Victoria Louie, Filippo Marchioni, Daniel Medina-Cleghorn, Isabel Morgado, Michael Mormino, Madeleine Nemchek, Erick Palomares, Rusha Sardhara, Julie Sheung, Sangita Sridharan, Gintvile Valinciute, Dipna Venkatachalam, Simon Vezina-Dawod, Derek Wodka, Stephanie Yung, Martin Eilers, John M. Maris, Yael P. Mossé, Martine F. Roussel, Elmar Wolf, Gwenn M. Hansen
Journal: Cancer Research (2025)

Abstract Aurora A kinase (AURKA) is an oncogene frequently overexpressed in adult solid tumors, hematologic malignancies, and pediatric cancers. AURKA plays an important role in mitosis, and cancer cells sensitive to loss of AURKA include lines derived from MYCN amplified tumors such as neuroblastoma, as well as those with RB1 loss such as neuroendocrine small cell cancers and CDK4/6-resistant breast cancer (Mou, et al., 2021). Several AURKA inhibitors are effective in preclinical tumor models, but this activity has 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. For example, AURKA limits the proteasomal degradation of MYCN through direct protein-protein interactions and prevents transcription/replication conflicts during S phase (Otto, et al, Cancer Cell, 2009; Buchel, et al., Cell Reports, 2017). To address the limitations of inhibitors, we have designed bifunctional targeted protein degraders of AURKA that enable removal of both enzymatic and scaffolding functions. Combinatorial chemical libraries of AURKA binders, CRBN binders, and linkers were generated by high-throughput parallel synthesis and screened for optimal properties in vitro and in vivo. These degraders form stable ternary complexes between AURKA and the E3 ligase CRBN, leading to efficient ubiquitylation and proteosome-dependent elimination of AURKA. Optimized AURKA degraders potently and selectively degraded AURKA in the MYCN amplified neuroblastoma cell line IMR32. Compounds with oral bioavailability and CNS exposure in mice were prioritized for further development. Our lead AURKA degrader, NRX-4972, has 58% oral bioavailability in C57BL/6 mice and moderate clearance (17.5 mL/min/kg). Three days of daily oral administration at 30 mg/kg to athymic nude mice bearing subcutaneous IMR32 tumors resulted in strong AURKA degradation (84% degraded relative to vehicle controls 6 hours after the final administration), high exposure in plasma (6.94 µM) and tumors (6,939 ng/g) and brain exposure of 178 ng/g. The closely related kinase AURKB was not degraded. AURKA degradation also promoted rapid regression of IMR32 neuroblastoma tumors, while inhibitors only achieved stasis. Analysis of tumors isolated from treated mice revealed that AURKA degraders, but not inhibitors, rapidly induced DNA damage and apoptosis. The differentiated activity of AURKA degraders compared to enzymatic inhibitors in these preclinical studies suggests the potential for improved safety and efficacy in cancer patients. The ability of AURKA degraders to penetrate the CNS not only broadens their therapeutic potential to include pediatric brain cancers such as medulloblastoma but also offers a promising avenue for treating adult cancers with brain metastases, addressing an urgent unmet medical need. Citation Format: Hua Tian, Eric Wegrzyniak, Ya-Wen Lu, Jeffrey T. Mihalic, Ryan Rountree, Tina Acholla, Bikash Adhikari, Karthik Arumugam, Paul Auger, Graham Carlson, Robert Cass, Coleen E. Casey, Abhinav Chaterjee, Lorenz Eing, James Iuliano, Adrienne Le, Yifan Li, Victoria Louie, Filippo Marchioni, Daniel Medina-Cleghorn, Isabel Morgado, Michael Mormino, Madeleine Nemchek, Erick Palomares, Rusha Sardhara, Julie Sheung, Sangita Sridharan, Gintvile Valinciute, Dipna Venkatachalam, Simon Vezina-Dawod, Derek Wodka, Stephanie Yung, Martin Eilers, John M. Maris, Yael P. Mossé, Martine F. Roussel, Elmar Wolf, Gwenn M. Hansen. Identification of selective, orally bioavailable aurora A degraders for treatment of pediatric and adult cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6379.