NEO-811

NEO-811 is a potent, selective, and orally bioavailable molecular glue degrader designed to induce targeted degradation of a protein called ARNT, also known as HIF-1β, a member of the hypoxia inducible factor (HIF) family of transcription factors. ARNT is the obligate binding partner for several transcription factors including HIF-1α, HIF-2α and AhR, proteins that play a critical role in angiogenesis, proliferation and tumor immunity.

In cancers such as clear cell renal cell carcinoma (ccRCC), loss-of-function mutations of a protein called VHL leads to constitutive overactivation of HIF transcription, and this can reprogram cells to become cancerous. Because ARNT is at the heart of HIF signaling and is required for downstream signaling by multiple proteins, it is a key target to block the HIF pathway. NEO-811 works as a molecular glue by bringing ARNT into an E3 ubiquitin ligase complex, which is part of the normal cellular protein recycling machinery. Once ARNT is bound to the E3 ubiquitin ligase complex, a tag of ubiquitin proteins is added onto ARNT, and this marks the ARNT protein for degradation by the proteosome.

By blocking HIF signaling, we aim to target the Achilles heel in ccRCC, since these cancer cells are addicted to dysregulated HIF activity, and normal cells are not. In this way, our molecular glue degrader, NEO-811, has the potential to address underlying tumor biology that remains inadequately treated with current standards of care. In preclinical studies, NEO-811 demonstrates potent suppression of HIF-2α target genes, including cyclin D and VEGF, along with additional activities by blocking the activity of HIF-1α and AhR. NEO-811 is currently being evaluated as a monotherapy in a first-in-human Phase 1/2 clinical trial in patients with locally advanced or metastatic non-resectable ccRCC.