9D6L

Human Sec61 complex inhibited by KZR-261

これはPDB形式変換不可エントリーです。

9D6L の概要

• エントリーDOI: 10.2210/pdb9d6l/pdb
• EMDBエントリー: 46597
• 分子名称: Protein transport protein Sec61 subunit gamma, Protein transport protein Sec61 subunit beta, Protein transport protein Sec61 subunit alpha isoform 1, ... (4 entities in total)
• 機能のキーワード: sec61, translocon, translocation, endoplasmic reticulum, secretion, membrane protein
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 70707.28

構造登録者

Park, E.,Wang, L. (登録日: 2024-08-15, 公開日: 2025-07-23, 最終更新日: 2025-07-30)

主引用文献

Lowe, E.,Anderl, J.L.,Bade, D.,Delgado-Martin, C.,Dong, C.,Fan, R.A.,Fang, Y.,Jiang, J.,Johnson, H.W.B.,Kempema, A.,McGilvray, P.,McMinn, D.,Millare, B.,Muchamuel, T.,Poweleit, N.,Qian, Y.,Rehan, S.,Scapin, G.,Sugahara, A.,Tranter, D.,Tuch, B.,Wang, J.,Wang, L.,Whang, J.A.,Zuno-Mitchell, P.,Paavilainen, V.O.,Park, E.,Taunton, J.,Kirk, C.J.,Anand, N.K.
Preclinical characterization of novel multi-client inhibitors of Sec61 with broad antitumor activity.
J.Pharmacol.Exp.Ther., 392:103634-103634, 2025

PubMed 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.

PubMed: 40669140
DOI: 10.1016/j.jpet.2025.103634

実験手法

ELECTRON MICROSCOPY (3.1 Å)