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Preclinical characterization of novel multi-client inhibitors of Sec61 with broad antitumor activity
Eric Lowe1, Janet L Anderl1, David Bade1
1Kezar Life Sciences, South San Francisco, California.
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.
Insights
Novel small molecules KZR-834 and KZR-261 inhibit the Sec61 translocon, blocking cancer-promoting protein production. KZR-261 shows promise in preclinical and early clinical trials for cancer therapy.
Area of Science:
- Molecular Biology
- Oncology
- Drug Discovery
Background:
- The Sec61 translocon is crucial for protein entry into the endoplasmic reticulum and represents a potential therapeutic target for cancer.
- Existing Sec61 inhibitors often have poor tolerability and suboptimal pharmaceutical properties, limiting their clinical development.
Purpose of the Study:
- To discover and characterize novel small molecule inhibitors of the Sec61 translocon with improved therapeutic potential.
- To evaluate the anticancer activity and tolerability of these novel inhibitors in preclinical and clinical settings.
Main Methods:
- Discovery and characterization of KZR-834 and KZR-261, small molecule analogs targeting the Sec61 channel.
- Assessment of Sec61 client protein inhibition, endoplasmic reticulum stress response activation, and in vitro anticancer effects.
- Evaluation of in vivo antitumor efficacy and tolerability of KZR-261 in various cancer models, including combination therapy with anti-PD-1 immunotherapy.
- Phase I clinical trial (NCT05047536) to assess safety, tolerability, and preliminary efficacy of KZR-261 in patients with malignant disease.
Main Results:
- KZR-834 and KZR-261 potently inhibit Sec61 channel function, affecting the biogenesis of specific Sec61 client proteins, including tumorigenic factors.
- Inhibition of Sec61 clients activated an endoplasmic reticulum stress response and demonstrated broad in vitro anticancer effects.
- KZR-261 was well tolerated in vivo and exhibited significant antitumor activity as a single agent and in combination with anti-PD-1 immunotherapy.
- Phase I clinical trial data indicated that KZR-261 was well tolerated at doses achieving durable stable disease in patients with malignant disease.
Conclusions:
- Sec61 inhibition represents a novel and promising therapeutic strategy for cancer treatment.
- KZR-261 demonstrates favorable tolerability and efficacy in preclinical models and early-phase clinical trials, highlighting its potential for broader application.
- This approach offers a new mechanism to block oncogenic factors, including those difficult to target with conventional therapies.
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