A first-in-human, open-label, multicenter, Phase 1 study of KZR-261 designed to assess the safety and tolerability, preliminary anti-tumor activity, and pharmacokinetics (PK) of KZR-261, as well as identify the recommended Phase 2 dose (RP2D). The study comprises a Part 1 (Dose Escalation) and a Part 2 (Dose Expansion) in solid organ tumors (melanoma/uveal melanoma, mesothelioma, colorectal cancer, prostate cancer, and "All-Tumors").

Start Date30 Sep 2021

Sponsor / Collaborator

Kezar Life Sciences, Inc.

100 Clinical Results associated with Sec61

100 Translational Medicine associated with Sec61

0 Patents (Medical) associated with Sec61

Literatures (Medical) associated with Sec61

01 Oct 2023·Journal of Dental Sciences

SEC61 translocon subunit gamma enhances low-dose cisplatin-induced cancer-stem cell properties of head and neck squamous cell carcinoma via enhancing Ca2+-mediated autophagy

Article

Author: Wang, Wenlong ; Sun, Legang ; Sun, Hengyan ; Bu, Xiangbin ; Ma, Xiangrui ; Zhang, Jun

Background/purposeHigh SEC61 translocon subunit gamma (SEC61G) expression is associated with an unfavorable prognosis in patients with head and neck squamous cell carcinoma (HNSCC), but the underlying mechanisms remain poorly understood.Materials and methodsHNSCC representative cell lines SCC15 and CAL27 were used to explore the regulation of SEC61G on Ca²⁺ leak from the endoplasmic reticulum (ER). Ca^2+-activated autophagy was monitored by fluorescent labeling of autophagosomes and western blotting assays. CSC marker expression, sphere formation, colony formation, and transwell of invasion were detected to investigate the role of SEC61G in regulating cancer-stem cell (CSC) properties.ResultsAmong the SEC61 complex genes, only SEC61G upregulation is consistently associated with unfavorable progression-free interval and disease-specific survival in patients with HNSCC. Low-dose cisplatin (CDDP) treatment induced SEC61G upregulation in SCC15 and CAL27 cells. SEC61G knockdown significantly impaired CDDP-induced Ca²⁺ from the ER and the phosphorylation of ERK1/2 and AMPK. CDDP-induced autophagy in HNSCC cells were hampered by SEC61G shRNA, in terms of impaired autophagosome formation, lowered LC3-II/GAPDH ratio and restored p62 expression. CDDP-induced CSC properties, including CSC marker expression, sphere formation, colony formation, and invasive capabilities could be suppressed by shSEC61G and chloroquine, a specific autophagy inhibitor.ConclusionFindings of this study revealed the contribution of SEC61G in promoting cisplatin-induced CSC properties of HNSCC cells via promoting Ca²⁺-mediated autophagy.

01 Jul 2023·Journal of cell science

Membrane insertases at a glance.

Article

Author: Kizmaz, Büsra ; Herrmann, Johannes M

Protein translocases, such as the bacterial SecY complex, the Sec61 complex of the endoplasmic reticulum (ER) and the mitochondrial translocases, facilitate the transport of proteins across membranes. In addition, they catalyze the insertion of integral membrane proteins into the lipid bilayer. Several membrane insertases cooperate with these translocases, thereby promoting the topogenesis, folding and assembly of membrane proteins. Oxa1 and BamA family members serve as core components in the two major classes of membrane insertases. They facilitate the integration of proteins with α-helical transmembrane domains and of β-barrel proteins into lipid bilayers, respectively. Members of the Oxa1 family were initially found in the internal membranes of bacteria, mitochondria and chloroplasts. Recent studies, however, also identified several Oxa1-type insertases in the ER, where they serve as catalytically active core subunits in the ER membrane protein complex (EMC), the guided entry of tail-anchored (GET) and the GET- and EMC-like (GEL) complex. The outer membrane of bacteria, mitochondria and chloroplasts contain β-barrel proteins, which are inserted by members of the BamA family. In this Cell Science at a Glance article and the accompanying poster, we provide an overview of these different types of membrane insertases and discuss their function.

01 Apr 2023·Cold Spring Harbor Perspectives in Biology

The Biogenesis of Multipass Membrane Proteins

Review

Author: Smalinskaitė, Luka ; Hegde, Ramanujan S

Multipass membrane proteins contain two or more α-helical transmembrane domains (TMDs) that span the lipid bilayer. They are inserted cotranslationally into the prokaryotic plasma membrane or eukaryotic endoplasmic reticulum membrane. The Sec61 complex (SecY complex in prokaryotes) provides a ribosome docking site, houses a channel across the membrane, and contains a lateral gate that opens toward the lipid bilayer. Model multipass proteins can be stitched into the membrane by iteratively using Sec61's lateral gate for TMD insertion and its central pore for translocation of flanking domains. Native multipass proteins, with their diverse TMDs and complex topologies, often also rely on members of the Oxa1 family of translocation factors, the PAT complex chaperone, and other poorly understood factors. Here, we discuss the mechanisms of TMD insertion, highlight the limitations of an iterative insertion model, and propose a new hypothesis for multipass membrane protein biogenesis based on recent findings.

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