Clinical Development of HC-7366
Activation of GCN2 by HC-7366 results in significant antitumor efficacy as monotherapy in multiple solid and hematological malignancies. HC-7366 also demonstrates enhanced combinatorial efficacy with varied standard of care agents such as HIF-2a antagonists, anti-BCL2 and anti-EGFR-TKIs.
HC-7366 is under investigation in a Phase 1a/b trial as monotherapy for treatment of advanced solid tumors. We have initiated the Phase 1b portion of our solid tumor study in RCC and plan to initiate additional Phase 1b combination studies in renal cell carcinoma (RCC) and in acute myeloid leukemia (AML).
GCN2 and the Integrated Stress Response
- GCN2 (General Controlled Nonderepressible 2), one of the kinases in the ISR family, responds to amino acid deprivation and is a key metabolic stress sensor in cells
- While cancer cells are known to utilize ISR for survival, prolonged or hyper activation of ISR has been shown to induce apoptosis
- Activated GCN2 phosphorylates eIF2⍺ and enhances ATF4 translation resulting in either survival or apoptosis in a context-dependent manner
- Hyperactivation of the ISR via GCN2 results in anti-tumor activity
- GCN2 is implicated in maintaining an immunosuppressive microenvironment
- Activation of GCN2 by HC-7366 results in anti-tumor activity by lethal activation of the ISR – Inhibition of protein translation, downmodulation of oncogenic proteins, and induction of mitochondrial dysfunction are some of the mechanistic characteristics
- HC-7366, a First-in-Human GCN2 activator, is currently in a Phase I clinical trial focused on solid tumors