Last update 01 Nov 2024

ZFP91

Last update 01 Nov 2024

Basic Info

Synonyms

E3 ubiquitin-protein ligase ZFP91, PZF, RING-type E3 ubiquitin transferase ZFP91

+ [8]

Introduction

Atypical E3 ubiquitin-protein ligase that mediates 'Lys-63'-linked ubiquitination of MAP3K14/NIK, leading to stabilize and activate MAP3K14/NIK. It thereby acts as an activator of the non-canonical NF-kappa-B2/NFKB2 pathway. May also play an important role in cell proliferation and/or anti-apoptosis.

Drugs associated with ZFP91

XD2-149

Target

ZFP91

Mechanism

ZFP91 gene modulators [+1]

Active Org.

University of Michigan

Originator Org.

University of Michigan

Active Indication

Neoplasms

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

SRT-152

Target

ZFP91

Mechanism

ZFP91 gene modulators

Active Org.

Smart Therapeutics, Inc.

Originator Org.

Smart Therapeutics, Inc.

Active Indication

Myotonic Dystrophy

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

AEV-003

Target

ZFP91

Mechanism

ZFP91 gene modulators

Active Org.

AevisBio, Inc.Startup

Originator Org.

AevisBio, Inc.Startup

Active Indication

Alzheimer Disease [+1]

Inactive Indication

Craniocerebral Trauma

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with ZFP91

100 Translational Medicine associated with ZFP91

0 Patents (Medical) associated with ZFP91

Literatures (Medical) associated with ZFP91

01 Jan 2024·Translational Oncology

MALAT1 promotes FOXA1 degradation by competitively binding to miR-216a-5p and enhancing neuroendocrine differentiation in prostate cancer

Article

Author: Luo, Liumei ; Kang, Xinli ; Song, Mi ; Wu, Qinghui ; Yang, Jing ; Zeng, Fanchang ; Ou, Zhewen ; Li, Daoyuan ; Yang, Zuobing

OBJECTIVESProstate cancer (PC) is a leading cause of cancer-related death in males worldwide. Neuroendocrine differentiation (NED) is a feature of PC that often goes undetected and is associated with poor patient outcomes. Long non-coding RNAs (lncRNAs), microRNAs (miRNAs/miRs), and messenger RNAs (mRNAs) play important roles in the development and progression of PC.METHODSIn this study, we used transcriptome sequencing and bioinformatics analysis to identify key regulators of NED in PC. Specifically, we examined the expression of PC-related lncRNAs, miRNAs, and mRNAs in PC cells and correlated these findings with NED phenotypes.RESULTSOur data revealed that metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) and zinc finger protein 91 (ZFP91) were upregulated in PC, while miR-216a-5p was down-regulated. Ectopic expression of MALAT1 induced NED and promoted malignant phenotypes of PC cells. Furthermore, we found that MALAT1 competitively bound to miR-216a-5p, upregulated ZFP91, and promoted the degradation of forkhead box A1 (FOXA1), a key gene involved in NED of PC.CONCLUSIONTaken together, these results suggest that MALAT1 plays an oncogenic role in NED and metastasis of PC via the miR-216a-5p/ZFP91/FOXA1 pathway. Our study highlights the potential of targeting this pathway as a novel therapeutic strategy for PC.

01 Dec 2022·eBioMedicine

Atypical E3 ligase ZFP91 promotes small-molecule-induced E2F2 transcription factor degradation for cancer therapy

Article

Author: Zhuo, Fang-Fang ; Zeng, Ke-Wu ; Liu, Dan ; Guo, Qiang ; Yang, Heng ; Liu, Yang ; Yang, Zhuo ; Zhao, Mei-Mei ; Tu, Peng-Fei ; Liu, Ting-Ting

BACKGROUNDThe E2F family of transcription factors play a crucial role in the development of various cancers. However, E2F members lack targetable binding pockets and are typically considered "undruggable". Unlike canonical small-molecule therapeutics, molecular glues mediate new E3 ligase-protein interactions to induce selective proteasomal degradation, which represents an attractive option to overcome these limitations.METHODSHuman proteome microarray was utilized to identify a natural product-derived molecular glue for targeting E2F2 degradation. Co-IP analysis with stable isotope labeling of amino acids in cell culture (SILAC)-based quantitative proteomics was carried out to further explore the E3 ligase for E2F2 degradation.FINDINGSIn this study, we identified a molecular glue bufalin, which significantly promoted E2F2 degradation. Unexpectedly, E2F2 underwent ubiquitination and proteasomal degradation via a previously undisclosed atypical E3 ligase, zinc finger protein 91 (ZFP91). In particular, we observed that bufalin markedly promoted E2F2-ZFP91 complex formation, thereby leading to E2F2 polyubiquitination via K48-linked ubiquitin chains for degradation. E2F2 degradation subsequently caused transcriptional suppression of multiple oncogenes including c-Myc, CCNE1, CCNE2, MCM5 and CDK1, and inhibited hepatocellular carcinoma growth in vitro and in vivo.INTERPRETATIONCollectively, our findings open up a new direction for transcription factors degradation by targeting atypical E3 ligase ZFP91. Meanwhile, the chemical knockdown strategy with molecular glue may promote innovative transcription factor degrader development in cancer therapy.FUNDINGThis work was financially supported by the National Key Research and Development Project of China (2022YFC3501601), National Natural Sciences Foundation of China (81973505, 82174008, 82030114), and China Postdoctoral Science Foundation (2019M650396), the Fundamental Research Funds for the Central Universities.

01 Dec 2022·European Journal of Medicinal Chemistry

Discovery and characterization of novel potent BCR-ABL degraders by conjugating allosteric inhibitor

Article

Author: Jiang, Biao ; Liu, Haixia ; Mi, Qianglong ; Ji, Liting ; Zhou, Yongqi ; Liu, Linyi ; Shen, ShuTing ; Shao, YuBao ; Ren, Chaowei ; Chen, Jinju ; Yin, Qianqian ; Zhang, Heqiao ; Bai, Fang ; Yang, Xiaobao ; Lin, Chencen ; Ding, Xinyu

The oncogenic fusion protein BCR-ABL is the driving force of leukemogenesis in chronic myeloid leukemia (CML). Despite the great advance in CML treatment through the application of tyrosine kinase inhibitors (TKIs) against BCR-ABL, disease recurrence after TKI discontinuation and clinical resistance mainly due to BCR-ABL mutations continue to be an issue. Herein we report our efforts to synthesize a novel series of CRBN-recruiting proteolysis-targeting chimeras (PROTACs) targeting BCR-ABL based on the allosteric inhibitor asciminib. Our efforts have led to the discovery of compound 30 (SIAIS100) through extensive SAR studies by the optimization of linker parameters as well as linker attachment points of both target-binding warhead and CRBN ligands, which exhibited the most potent degradative activity with a DC₅₀ value of 2.7 nM and D_max of 91.2% against BCR-ABL and has an IC₅₀ value of 12 nM in BCR-ABL ⁺ K562 cells. The binding model and the stability evaluation of 30-induced ternary complex formation were also elucidated through computational simulations. Furthermore, 30 induced sustained and robust BCR-ABL degradation and maintained the efficacy for 96 h post-washout. Moreover, the proteomics analysis showed that 30 degraded BCR-ABL and three CRBN's neo-substrates, including IKZF1, IKZF3, and ZFP91. Additionally, 30 also exerted degradative activity against a panel of clinically relevant resistance-conferring mutations of BCR-ABL, including gatekeeper mutation T315I, several single mutations associated with TKI resistance, and certain highly resistant compound mutations. Our study provided a deeper understanding of the development of PROTACs targeting BCR-ABL and novel potential therapeutic agents for CML treatment.

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