Last update 19 Sep 2024

UCHL5

Last update 19 Sep 2024

Basic Info

Synonyms

CGI-70, INO80 complex subunit R, INO80R

+ [8]

Introduction

Protease that specifically cleaves 'Lys-48'-linked polyubiquitin chains. Deubiquitinating enzyme associated with the 19S regulatory subunit of the 26S proteasome. Putative regulatory component of the INO80 complex; however is inactive in the INO80 complex and is activated by a transient interaction of the INO80 complex with the proteasome via ADRM1.

Drugs associated with UCHL5

VLX-1570

Target

UCHL5 x USP14

Mechanism

UCHL5 inhibitors [+1]

Active Org.-

Originator Org.

Vivolux AB

Active Indication-

Inactive Indication

Bone Marrow Neoplasms [+2]

Drug Highest PhaseDiscontinued

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

VLX-600

Target

UCHL5 x USP14

Mechanism

UCHL5 inhibitors [+1]

Active Org.-

Originator Org.

Karolinska Institutet

Active Indication-

Inactive Indication

Refractory Cancer [+1]

Drug Highest PhaseDiscontinued

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

b-AP15

Target

19S proteasome x UCHL5 x USP14

Mechanism

19S proteasome inhibitors [+2]

Active Org.-

Originator Org.

Karolinska Institutet

Active Indication-

Inactive Indication

Adult Acute Myeloblastic Leukemia

Drug Highest PhasePending

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

Clinical Trials associated with UCHL5

NCT02372240 / TerminatedPhase 1/2

VLX1570 and Low-Dose Dexamethasone in Relapsed or Relapsed and Refractory Multiple Myeloma: A Clinical and Correlative Phase 1/2 Study

This is a phase 1/2 single arm study to determine the safety and efficacy of VLX1570 IV infusion administered with low dose dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma.

Start Date08 Apr 2015

Sponsor / Collaborator

Vivolux AB

[+1]

NCT02222363 / TerminatedPhase 1

A Phase I Study of the Safety and Tolerability of VLX600, an Iron Chelator, in Patients With Refractory Advanced Solid Tumors

The purpose of this study is to evaluate the safety and tolerability of the investigational drug VLX600 in patients with refractory advanced solid tumors.

Start Date18 Feb 2015

Sponsor / Collaborator

Vivolux AB

[+1]

100 Clinical Results associated with UCHL5

100 Translational Medicine associated with UCHL5

0 Patents (Medical) associated with UCHL5

306

Literatures (Medical) associated with UCHL5

01 Jul 2024·Indian Dermatology Online Journal

Changes in the Cutaneous Nerve Fiber Staining and Distribution of PGP9.5 in Clinically Uninvolved Skin in Leprosy Patients after Completion of Multidrug Therapy and Assessing PGP9.5 as a Marker of Treatment Response

Article

Author: Sharma, Ankur ; Dogra, Sunil ; Narang, Tarun ; Thakur, Vishal ; Razmi, T Muhammad ; Dhawan, Garima ; Modi, Manish ; Bishnoi, Anuradha ; Handa, Sanjeev ; Saikia, Uma Nahar

AbstractBackground:Subclinical involvement of nerves may sometimes be present much before the overt clinical manifestations become apparent. Protein gene product (PGP) 9.5, a ubiquitin-C-terminal hydrolase, has been widely used as a marker to study the involvement of peripheral nerve fibers in many diseases.Aim and Objectives:To evaluate the change in cutaneous nerve fiber staining and distribution from pre-treatment and post completion of multidrug therapy through the expression of PGP9.5 and to assess PGP9.5 as a marker of treatment response.Materials and Methods:In this prospective single-center observational study, skin biopsy was taken in patients with leprosy, having areas of nerve function impairment (NFI), based on findings of nerve conduction studies (NCSs), but not having lesions or impaired tactile or thermal impairment clinically. The thin nerve fiber density in the clinically normal skin in areas supplied by nerve showing changes of sensory neuropathy was evaluated to study the density of the fibers. A second biopsy was taken at the end of treatment from a site near the previous site to assess the changes in intra-epidermal nerve fiber staining and distribution.Results:Thirty-three patients were recruited in the present study (24 males and 9 females). Pre-treatment, 27 patients had abnormal NCSs, while six patients did not have any evidence of neuropathy on NCSs. Staining for nerve fibers using PGP9.5; in the epidermis was positive in five patients pre-treatment and 11 patients post treatment (P = 0.181). Staining in the dermis revealed positivity in 14 pre-treatment, which increased to 18 post treatment (P = 0.342). Adnexae showed positivity in five patients pre-treatment and increased to 17 post treatment (P = 0.005).Conclusion:A reduced PGP9.5 staining in the epidermal, dermal, and adnexal regions was seen in leprosy patients, which improved post treatment. Thus, PGP9.5 may serve as a marker of NFI and treatment response.

01 Dec 2023·Acta Pharmacologica Sinica

Targeting proteasomal deubiquitinases USP14 and UCHL5 with b-AP15 reduces 5-fluorouracil resistance in colorectal cancer cells

Article

Author: Chen, Xin ; Wang, Jin-Xiang ; Zhou, Huan ; Tang, Dao-Lin ; Wu, Jun-Zheng ; Liu, Bing-Yuan ; Jiang, Li-Ling ; Shi, Xian-Ping ; Ding, Wa ; Meng, Yi ; Lou, En-Zhe ; Liu, Ao-Chu ; Liu, Jin-Bao ; Peng, Guan-Jie ; Zhang, Hai-Chuan ; Mao, Qiong

5-Fluorouracil (5-FU) is the first-line treatment for colorectal cancer (CRC) patients, but the development of acquired resistance to 5-FU remains a big challenge. Deubiquitinases play a key role in the protein degradation pathway, which is involved in cancer development and chemotherapy resistance. In this study, we investigated the effects of targeted inhibition of the proteasomal deubiquitinases USP14 and UCHL5 on the development of CRC and resistance to 5-FU. By analyzing GEO datasets, we found that the mRNA expression levels of USP14 and UCHL5 in CRC tissues were significantly increased, and negatively correlated with the survival of CRC patients. Knockdown of both USP14 and UCHL5 led to increased 5-FU sensitivity in 5-FU-resistant CRC cell lines (RKO-R and HCT-15R), whereas overexpression of USP14 and UCHL5 in 5-FU-sensitive CRC cells decreased 5-FU sensitivity. B-AP15, a specific inhibitor of USP14 and UCHL5, (1-5 μM) dose-dependently inhibited the viability of RKO, RKO-R, HCT-15, and HCT-15R cells. Furthermore, treatment with b-AP15 reduced the malignant phenotype of CRC cells including cell proliferation and migration, and induced cell death in both 5-FU-sensitive and 5-FU-resistant CRC cells by impairing proteasome function and increasing reactive oxygen species (ROS) production. In addition, b-AP15 inhibited the activation of NF-κB pathway, suppressing cell proliferation. In 5-FU-sensitive and 5-FU-resistant CRC xenografts nude mice, administration of b-AP15 (8 mg·kg^-1·d^-1, intraperitoneal injection) effectively suppressed the growth of both types of tumors. These results demonstrate that USP14 and UCHL5 play an important role in the development of CRC and resistance to 5-FU. Targeting USP14 and UCHL5 with b-AP15 may represent a promising therapeutic strategy for the treatment of CRC.

28 Nov 2023·Analytical Chemistry

Uncovering DUB Selectivity through an Ion Mobility-Based Assessment of Ubiquitin Chain Isomers

Article

Author: Shestoperova, Elizaveta I ; Strieter, Eric R

Ubiquitination is a reversible post-translational modification that maintains cellular homeostasis and regulates protein turnover. Deubiquitinases (DUBs) are a large family of proteases that catalyze the removal of ubiquitin (Ub) along with the dismantling and editing of Ub chains. Assessing the activity and selectivity of DUBs is critical for defining physiological functions. Despite numerous methods for evaluating DUB activity, none are capable of assessing activity and selectivity in the context of multicomponent mixtures of native unlabeled Ub conjugates. Here, we report an ion mobility (IM)-based approach for measuring DUB selectivity in the context of unlabeled mixtures of Ub chains. We show that IM-mass spectrometry (IM-MS) can be used to assess the selectivity of DUBs in a time-dependent manner. Moreover, using the branched Ub chain selective DUB UCH37/UCHL5 along with a mixture of Ub trimers, a strong preference for branched Ub trimers bearing K6 and K48 linkages is revealed. Our results demonstrate that IM-MS is a powerful method for evaluating DUB selectivity under conditions more physiologically relevant than single-component mixtures.

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UCHL5

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