KZR-834

SIGNIFICANCE STATEMENT: KZR-834 and KZR-261 are novel Sec61 inhibitors with the ability to block multiple Sec61 client proteins, leading to well-tolerated efficacy in in vivo cancer models. This represents a novel mechanism for blocking expression of oncogenic factors, including those not amenable to targeting through conventional methods.

KZR-261 is a first-in-class small molecule Sec61 inhibitor currently in a Phase I clinical trial in patients with advanced solid tumors (NCT05047536). Specifically, in the MC38 tumor model, KZR-834 combines with anti-PD-1 antibody to enhance immune responses. These data support further investigation into combining KZR-834 with immune checkpoint inhibitors to potentiate anti-tumor activity.

Anti-tumor activity of KZR-834, a structurally related analog of KZR-261, was assessed in two cell line cytotoxicity screens totaling over 400 cell lines. Our novel small molecule inhibitors of Sec61 dependent protein translocation exhibit broad anti-tumor activity in vitro. Large cell line screens and bioinformatic analyses identifying tumor intrinsic sensitivities led to a prioritized list of potentially sensitive tumor types that has guided tumor type selection for our initial Phase 1 clinical trial of KZR-261 in solid tumors.

The structural analogs KZR-261 and KZR-834 were identified through a medicinal chemistry campaign and found to have broad in vitro anti-tumor activity and efficacy in mouse xenograft models. Flow cytometric analysis of PBMCs also showed a significant reduction in surface expression of those proteins in multiple cell populations.Our results highlight quantitative proteomic profiling as a valuable tool towards elucidation of the mechanism of pleiotropically-acting molecules. By assessing global proteomic changes in non-transformed cells, pharmacodynamic markers were identified that will be employed in the Phase 1 trial of KZR-261 in solid tumors.