KZR-834 / Kezar - LARVOL DELTA

Preclinical characterization of novel multi-client inhibitors of Sec61 with broad antitumor activity. (PubMed, J Pharmacol Exp Ther) - P1 | "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."

IO biomarker • Journal • Preclinical • Oncology • SEC61G

Quantitative proteomic profiling of KZR-540, a novel small molecule oral Sec61 inhibitor that selectively inhibits PD-1 expression (SITC 2023) - P1 | "1 Here we utilized LC/MS-based quantitative proteomic profiling to study the unique selectivity of KZR-540 in contrast to the promiscuous Sec61 inhibitor KZR-261 and its analog KZR-834. KZR-261 is currently being evaluated in a phase-1 clinical trial in solid tumors (NCT05047536). Follow-up in vivo studies will examine the differential impact of KZR-540 and KZR-261/834 on the tumor-draining lymph nodes (TDLNs) and plasma proteomes of human-PD-1 knock-in mice bearing human-PD-L1 MC38 tumors."

IO biomarker • Oncology • Solid Tumor • PD-L1 • SEC61G

Sec61 inhibitor KZR-834, an anti-cancer agent, exhibits immunomodulatory activity and combines with PD-1 blockade to further enhance immune responses (AACR 2022) - P1 | "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."

IO biomarker • Colon Cancer • Gastrointestinal Cancer • Hematological Malignancies • Oncology • Solid Tumor • CD44 • CD69 • CD8 • CD86 • IFNG • IL2RA • PD-L1 • SEC61G

[VIRTUAL] Prioritizing tumor types for clinical study of novel Sec61 inhibitors by searching for expression profiles of sensitive cell lines in tumor sample databases (AACR 2021) - "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."

Preclinical • Cutaneous Melanoma • Diffuse Large B Cell Lymphoma • Lung Cancer • Melanoma • Mesothelioma • Oncology • Solid Tumor • CCND2

[VIRTUAL] Quantitative proteomic profiling of novel anti-cancer small molecule inhibitors of Sec61: Mechanistic investigation and biomarker discovery (AACR 2021) - "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."

Biomarker • Oncology • Solid Tumor • B2M • ICAM1 • IL7