2. Academic Validation
  3. Preclinical characterization of novel multi-client inhibitors of Sec61 with broad antitumor activity

Preclinical characterization of novel multi-client inhibitors of Sec61 with broad antitumor activity

  • J Pharmacol Exp Ther. 2025 Jun 14;392(8):103634. doi: 10.1016/j.jpet.2025.103634.
Eric Lowe 1,  Janet L Anderl 1,  David Bade 1,  Cristina Delgado-Martin 1,  Chengguo Dong 1,  R Andrea Fan 1,  Ying Fang 1,  Jing Jiang 1,  Henry W B Johnson 1,  Aaron Kempema 1,  Phil McGilvray 2,  Dustin McMinn 1,  Beatriz Millare 1,  Tony Muchamuel 1,  Nicole Poweleit 2,  Yu Qian 1,  Shahid Rehan 3,  Giovanna Scapin 2,  Ajia Sugahara 1,  Dale Tranter 3,  Brian Tuch 1,  Jinhai Wang 1,  Laurie Wang 4,  Jennifer A Whang 1,  Patricia Zuno-Mitchell 1,  Ville O Paavilainen 3,  Eunyong Park 5,  Jack Taunton 6,  Christopher J Kirk 1,  Neel K Anand 7
Affiliations

Affiliations

  • 1 Kezar Life Sciences, South San Francisco, California.
  • 2 Nanoimaging, Woburn, Massachusetts.
  • 3 Institute of Biotechnology, HiLIFE, University of Helsinki, Helsinki, Finland.
  • 4 Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, California.
  • 5 Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, California; California Institute for Quantitative Biosciences, University of California, Berkeley, Berkeley, California.
  • 6 Department of Cellular and Molecular Pharmacology, University of California, San Francisco, California.
  • 7 Kezar Life Sciences, South San Francisco, California. Electronic address: nanand@kezarbio.com.
PMID: 40669140 DOI: 10.1016/j.jpet.2025.103634
Abstract

The Sec61 translocon mediates entry of most secreted and transmembrane proteins into the endoplasmic reticulum, providing a novel therapeutic target to block the expression of protumorigenic factors. Sec61 inhibitors with antitumor activity, mostly derived from natural products, have been reported. However, poor tolerability and suboptimal pharmaceutical properties have precluded their further development. We report here the discovery and characterization of KZR-834 and KZR-261, related small molecule analogs that directly bind to the Sec61 channel to potently inhibit the biogenesis of a subset of Sec61 client proteins. This client inhibition profile includes several tumorigenic factors, results in the activation of an endoplasmic reticulum stress response, and leads to broad Anticancer effects in vitro. In vivo, KZR-261 was well tolerated and exhibits antitumor effects across multiple models, both as a single agent and in combination with anti-PD-1 immunotherapy. Based on the strength of this preclinical data, KZR-261 progressed into a phase I clinical trial (NCT05047536) in patients with malignant disease, where it was found to be well tolerated at doses that achieved durable stable disease. These results highlight the potential of Sec61 inhibition as a novel therapeutic target. 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.

Keywords

Anticancer; Drug targets; Oncology; Small molecule.

Figures
Products