Sec61 inhibitors block protein translocation into the ER, leading to suppression of tumor growth and synergy with immunotherapy. KZR-261 and related small molecules bind the Sec61 translocon and selectively prevent the translocation of secreted and transmembrane proteins into the ER. This leads to reduced expression of oncogenic and immune regulatory proteins, activation of ER stress pathways, and tumor cell death. In preclinical models, KZR-261 demonstrated broad antitumor activity and showed augmented effects when combined with anti–PD-1 therapy. Collectively, these findings supported its advancement into early-phase clinical evaluation for solid tumors.
Sec61 inhibitors block protein translocation into the ER, leading to suppression of tumor growth and synergy with immunotherapy. KZR-261 and related small molecules bind the Sec61 translocon and selectively prevent the translocation of secreted and transmembrane proteins into the ER. This leads to reduced expression of oncogenic and immune regulatory proteins, activation of ER stress pathways, and tumor cell death. In preclinical models, KZR-261 demonstrated broad antitumor activity and showed augmented effects when combined with anti–PD-1 therapy. Collectively, these findings supported its advancement into early-phase clinical evaluation for solid tumors.
