Delving into the Latest Updates on Sabutoclax with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

BI-97C1, ONT 701, ONT-701

Target

Bcl-2 x Bcl-xl x Mcl-1

Mechanism

Bcl-2 inhibitors(Apoptosis regulator Bcl-2 inhibitors), Bcl-xl inhibitors(Apoptosis regulator Bcl-X inhibitors), Mcl-1 inhibitors(Induced myeloid leukemia cell differentiation protein Mcl-1 inhibitors)

Therapeutic Areas

NeoplasmsUrogenital Diseases

Active Indication-

Inactive Indication

Prostatic Cancer

Originator Organization

Sanford Burnham Prebys Medical Discovery Institute

Active Organization-

Inactive Organization

Sanford Burnham Prebys Medical Discovery Institute

Drug Highest PhasePendingPreclinical

First Approval Date-

Regulation-

Structure

Molecular FormulaC42H40N2O8

InChIKeyRAYNZUHYMMLQQA-UHFFFAOYSA-N

CAS Registry1228108-65-3

Transcriptomic expression data of STAD from GEO database, single cell sequencing data from OMIX gastric cancer database. Conservative molecular typing of gastric cancer was constructed using non‐negative matrix factorization (NMF). The abundance of 28 immune cells in the tumour samples was assessed using ssGSEA. The R package “oncoPredict” was used to predict chemotherapy response. TIDE website for immunotherapy response prediction. Finally, single cell analysis was performed to clarify the specific type annotation of STAD cells and to analysis their spatial expression.

Results:

Hypoxia‐score demonstrated excellent prognostic discrimination in TCGA gastric cancer samples. Among multiple deconvolution‐based algorithms for immune infiltration, Hypoxia‐score presented a general immunosuppressive efficacy across multiple datasets, as evidenced by a broad negative correlation with immune cell infiltration. By the likelihood that each group may have specific drug sensitivity to multiple chemotherapeutic and targeted agents. Results showed that high‐risk scoring patients were more sensitive to Staurosporine, Sabutoclax, and AZD8055, while low‐risk patients were more sensitive to Bortezomib, Dactinomycin, Docetaxel, Daporinad, Sepantronium, and bromide. In the immunotherapy cohort, the Hypoxia‐score presented the ability to discriminate for immunotherapy efficacy. The distribution of Hypoxia‐score in single‐cell descending space was calculated using AddModuleScore and was found to be distributed across the various cell types annotated in the single‐cell analysis. It is suggested that various cells in the tumour microenvironment are involved in hypoxia gene set processes to varying degrees.

Conclusion:

The Hypoxia‐score proves to be a valuable tool for assessing the prognosis of gastric cancer patients and guiding drug treatments, providing significant guidance for clinical diagnosis and treatment in the context of gastric cancer.

01 Sep 2023·Advanced healthcare materials

Coordination-Driven Self-Assembly of Biomedicine to Enhance Photodynamic Therapy by Inhibiting Proteasome and Bcl-2.

Article

Author: Chen, Zu-Xiao ; Cheng, Hong ; Chen, A-Li ; Wang, Rui-Xin ; Li, Peng-Fei ; Cai, Hua ; Zhao, Lin-Ping ; Li, Shi-Ying ; Xu, Lin ; Yang, Ni ; Zheng, Rong-Rong ; Huang, Yue-Kang

Tumor cells resist oxidative damage and apoptosis by activating defense mechanisms. Herein, a self-delivery biomedicine (designated as BSC) is developed by the self-assembly of Bortezomib (BTZ), Sabutoclax (Sab) and Chlorin e6 (Ce6). Interestingly, BTZ can be coordinated with Sab to promote the assembly of uniform ternary biomedicine through non-covalent intermolecular interactions. Moreover, BTZ as a proteasome inhibitor can prevent tumor cells from scavenging damaged proteins to reduce their oxidative resistance. Sab can downregulate B-cell lymphoma 2 (Bcl-2) to decrease the antiapoptotic protein. Both the proteasome and Bcl-2 inhibitions contribute to increasing cell apoptosis and amplifying photodynamic therapy (PDT) efficacy of Ce6. Encouragingly, carrier-free BSC receives all biological activities of these assembly elements, including photodynamic performance as well as inhibitory capabilities of proteasome and Bcl-2. Besides, BSC has a preferable cellular uptake ability and tumor retention property, which increase the drug delivery efficiency and bioavailability. In vitro and in vivo research demonstrate the superior PDT efficiency of BSC by proteasome and Bcl-2 inhibitions. Of special note, the coordination-driven self-assembly of BSC is pH-responsive, which can be disassembled for controlled drug release upon tumor acidic microenvironment. This study will expand the applicability of self-delivery nanomedicine with sophisticated mechanisms for tumor treatment.

15 Jan 2023·Aging

Profiling of a novel circadian clock-related prognostic signature and its role in immune function and response to molecular targeted therapy in pancreatic cancer

Article

Author: Gong, Shuang ; Jin, Yu ; Hu, Lilin ; Li, Gangping ; Shang, Guochen

BACKGROUND:

Pancreatic ductal adenocarcinoma (PADA) represents a devastating type of pancreatic cancer with high mortality. Defining a prognostic gene signature that can stratify patients with different risk will benefit cancer treatment strategies.

METHODS:

Gene expression profiles of PADA patients were acquired from the Cancer Genome Atlas and Gene Expression Omnibus, including GSE62452 and GSE28735. Differential expression analysis was carried out using the package edgeR in R. Intro-tumor immune infiltrates were quantified by six different computational algorithms XCELL, TIMER, QUANTISEQ, MCPCOUNTER, EPIC, and CIBERSORT. Biological processes were investigated based on R package "clusterProfiler".

RESULTS:

13 genes (ARNTL2, BHLHE40, FBXL17, FBXL8, PPP1CB, RBM4B, ADRB1, CCAR2, CDK1, CSNK1D, KLF10, PSPC1, SIAH2) were eligible for the development of a prognostic gene signature. Performance of the prognostic gene signature was assessed in the discovery set (n = 210), validation set (n = 52), and two external data set (GSE62452, n = 65, and GSE28735, n = 84). Area under the curve (AUC) for predicting 3-year overall survival was 0.727, 0.732, 0.700, and 0.658 in the training set, the validation set, and the two test sets, respectively. KM curve revealed that the low-risk group had an improved prognosis than the high-risk group in all four datasets. PCA analysis demonstrated that the low-risk group was apparently separated from the high-risk group. CD8 T cell and B cell were significantly reduced in the high-risk group than in the low-risk group, while neutrophils were significantly augmented in the high-risk group than in the low-risk group. BMS-536924, Foretinib, Linsitinib, and Sabutoclax were more sensitive in the low-risk group, whereas Erlotinib was more effective in the high-risk group.

CONCLUSIONS:

We successfully established and verified a novel circadian clock-related gene signature, which could stratify patients with different risk and be reflective of the therapeutic effect of molecular targeted therapy. Our findings could incorporate the pharmacological modulation of circadian clock into future therapeutic strategies.

100 Deals associated with Sabutoclax

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