作者: Miller, Jenna ; Rai, Ganesha ; Doleschal, Megan N. ; Simeonov, Anton ; Zakharov, Alexey V. ; Zhuang, Zhihao ; Jain, Sankalp ; Baljinnyam, Bolormaa

Ubiquitination is a post-translational modification that elicits a variety of cellular responses. Deubiquitinases (DUBs) remove ubiquitin moieties from proteins and modulate cellular processes by counteracting the ubiquitin ligase activities. Ubiquitination and deubiquitination processes are tightly regulated by different mechanisms and their dysregulation is associated with many diseases. Discovery of DUB inhibitors could not only lead to therapeutics but also facilitate the understanding of ubiquitination/deubiquitination processes and their regulatory mechanisms. To enable the inhibitor discovery against DUBs, we developed a cell-based DUB assay that utilizes a cell-permeable ubiquitin probe, Biotin-cR₁₀-Ub-PA, to covalently label DUBs in their native cellular environment. Amplified luminescent proximity homogeneous assay (Alpha, specifically AlphaLISA) is utilized to quantitatively assess the capture of the target DUB by the Biotin-cR₁₀-Ub-PA probe. We demonstrated that this new cell-based DUB assay is robust and amenable to high-throughput screening. Human USP15 was selected as a DUB of interest and screened against a library of protease inhibitors as a proof of concept. In addition to the widely adopted pan-DUB inhibitor PR-619, several other DUB inhibitors from the library were also identified as hits. This new DUB assay can be readily adapted for inhibitor discovery against many other human DUBs to identify potent and cell-permeable inhibitors.

2019-01-01·Bioorganic & medicinal chemistry letters4区 · 医学

Diarylcarbonates are a new class of deubiquitinating enzyme inhibitor

4区 · 医学

Article

作者: Long, Marcus J C ; Baggio, Rick ; Fasci, Domenico ; Lawson, Ann P ; Rozhansky, Lior ; El Oualid, Farid ; Hedstrom, Lizbeth ; Weerapana, Eranthie ; Qian, Yu

Promiscuous inhibitors of tyrosine protein kinases, proteases and phosphatases are useful reagents for probing regulatory pathways and stabilizing lysates as well as starting points for the design of more selective agents. Ubiquitination regulates many critical cellular processes, and promiscuous inhibitors of deubiquitinases (DUBs) would be similarly valuable. The currently available promiscuous DUB inhibitors are highly reactive electrophilic compounds that can crosslink proteins. Herein we introduce diarylcarbonate esters as a novel class of promiscuous DUB inhibitors that do not have the liabilities associated with the previously reported compounds. Diarylcarbonates stabilize the high molecular weight ubiquitin pools in cells and lysates. They also elicit cellular phenotypes associated with DUB inhibition, demonstrating their utility in ubiquitin discovery. Diarylcarbonates may also be a useful scaffold for the development of specific DUB inhibitors.

2017-06-27·PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA

Deubiquitinating enzyme VCIP135 dictates the duration of botulinum neurotoxin type A intoxication.

Article

作者: Tessarollo, Lino ; Kotiya, Archana ; Kiris, Erkan ; Weissman, Allan M ; Bavari, Sina ; Yang, Mei ; Tsai, Yien Che ; Oyler, George A

Botulism is characterized by flaccid paralysis, which can be caused by intoxication with any of the seven known serotypes of botulinum neurotoxin (BoNT), all of which disrupt synaptic transmission by endoproteolytic cleavage of SNARE proteins. BoNT serotype A (BoNT/A) has the most prolonged or persistent effects, which can last several months, and exerts its effects by specifically cleaving and inactivating SNAP25. A major factor contributing to the persistence of intoxication is the long half-life of the catalytic light chain, which remains enzymatically active months after entry into cells. Here we report that BoNT/A catalytic light chain binds to, and is a substrate for, the ubiquitin ligase HECTD2. However, the light chain evades proteasomal degradation by the dominant effect of a deubiquitinating enzyme, VCIP135/VCPIP1. This deubiquitinating enzyme binds BoNT/A light chain directly, with the two associating in cells through the C-terminal 77 amino acids of the light chain protease. The development of specific DUB inhibitors, together with inhibitors of BoNT/A proteolytic activity, may be useful for reducing the morbidity and public health costs associated with BoNT/A intoxication and could have potential biodefense implications.

项与 DUB inhibitor (Mission Therapeutics/Pfizer) 相关的新闻（医药）

2024-03-26

·BioSpace

Ubiquigent and Debiopharm Enter Agreement to Support USP1 Inhibitor Programme for Debio 0432

Project will be a demonstration of how Ubiquigent’s DUB-centric platform can support the development of DUB inhibitors all the way from discovery through to clinical development. DUNDEE, Scotland & LAUSANNE, Switzerland--(BUSINESS WIRE)-- Ubiquigent Limited (Ubiquigent), a drug discovery and development company harnessing novel deubiquitinase (DUB) modulators as new therapeutics for areas of high unmet medical need, today announced an agreement with Debiopharm, a biopharmaceutical company aiming to develop tomorrow’s standard-of-care treatments to cure cancer and infectious diseases. The agreement will support the development of Debiopharm’s USP1 inhibitor programme, Debio 0432. Under the terms of the agreement, Ubiquigent will deploy its DUB-focused platform, combined with its deep understanding of the DUB field, to develop novel target engagement assays to support Debio-0432 as it approaches the clinic. Currently, in late-stage preclinical development, Debio 0432 is a small molecule with best-in-class potential that could be deployed to combat multiple tumour types. Through its potent and selective inhibition of USP1, a critical player in the DNA damage repair (DDR) pathway, Debio 0432 has the potential to induce synthetic lethality in tumour types with underlying defects of DNA repair genes. “We are delighted to enter this agreement with Debiopharm, supporting the development of its advanced USP1 inhibitor programme. Following our successful collaborations with other clinical stage companies, this latest agreement further demonstrates the capability of Ubiquigent’s platform to address all aspects of DUB drug discovery and development, encompassing target validation, hit-to-lead, candidate selection, translational research, and the development of assays to support clinical evaluation.” Jason Mundin, CEO of Ubiquigent, said: “With multiple assets now reaching clinical stage, we look forward to seeing the continued progression and expansion of the DUB field over the coming years as more companies enter the space and new therapeutics enter the clinic.” Bertrand Ducrey, CEO, Debiopharm, commented: “Ubiquigent’s specialised drug discovery platform is uniquely positioned to support our USP1 inhibitor programme as it approaches the clinic, enabling the development of novel target engagement assays. Selective inhibition of USP1 to interrupt DNA damage repair pathway is an exciting approach to cancer treatment.” To learn more about Ubiquigent’s platform for DUB-focused drug discovery, visit: View source version on businesswire.com: Contacts Esmé Walters Zyme Communications E-mail: esme.walters@zymecommunications.com Phone: +44 (0) 7377 543244 Source: Ubiquigent View this news release online at:

引进/卖出临床研究

2024-03-14

·Firstwordpharma

Cambridge biotech raises £25M for mitophagy Mission more than a decade in the making

Mission Therapeutics’ strategy of boosting a natural cellular recycling process, called mitophagy, to treat neurodegenerative and mitochondria-related diseases has attracted £25.2 million ($32.1 million) in fresh funding. The biotech, which also boasts a pair of pharma partnerships, is focused on developing small molecule inhibitors of de-ubiquitylating enzymes (DUBs) – the brakes on the garbage disposal system. Since its founding in 2011, Mission has raised a total of £117 million. Thursday’s series D financing was jointly led by a syndicate of existing investors, including Pfizer Venture Investments. The pharma giant’s first investment in Mission was over a decade ago, and in 2020, Pfizer led a £12 million financing and also staked a claim on its DUB platform. Under the deal, Pfizer has the option to negotiate target exclusivity for certain, prespecified DUB inhibitors. The Cambridge-based biotech also has a 2018 tie-up with AbbVie for two DUB programmes to treat Alzheimer’s disease. Other backers of the round include Sofinnova Partners, Roche Venture Fund, SR One, IP Group, and Rosetta Capital.DUB developmentWhile DUBs’ role in mitophagy-associated diseases is well established, they have been historically difficult to selectively and specifically target with small molecules, as they comprise a large family of proteins. Mission’s lead candidate, MTX652, is in Phase II testing for acute kidney injury (AKI) associated with cardiac surgery. Thursday’s round will help progress the company’s second candidate, MTX325, which has been cleared to start a Phase I trial for Parkinson’s disease (PD) in the UK. Both programmes target USP30, a key DUB in the regulation of mitophagy. According to Mission, USP30 inhibition can promote the degradation of disease-associated proteins and impaired mitochondria, potentially improving cellular health and longevity. If cells don’t routinely recycle their mitochondria, an accumulation of the dysfunctional organelles can lead to cellular degeneration, particularly of neurons. Mitochondrial dysfunction is a key driver of PD mechanisms, Mission CEO Anker Lundemose told FirstWord. Inhibiting USP30 to promote mitophagy is “likely to have a positive impact on dopaminergic neurons undergoing chronic degenerative processes, as such degeneration results in functional impairment,” Lundermose added.Mission has shown that, in a mouse model of PD, USP30 inhibition can help protect against loss of dopamine and dopaminergic neurons induced by alpha-synuclein.

临床2期临床1期

2024-03-11

·BioSpace

Ubiquigent Enters Agreement With Astellas Subsidiary, Nanna Therapeutics

Agreement leverages Ubiquigent’s DUB-focused drug discovery platform to support the development of novel therapeutic candidates for multiple disease targets selected by Nanna Therapeutics DUNDEE, Scotland--(BUSINESS WIRE)-- Ubiquigent Limited (Ubiquigent), a drug discovery and development company harnessing novel deubiquitinase (DUB) modulators as new therapeutics for areas of high unmet medical need, today announced an agreement with Nanna Therapeutics (Nanna). Under the terms of the agreement, Ubiquigent will provide Nanna with access to its deubiquitylase (DUB) focused drug discovery platform to support the development of novel therapeutics for human disease targets selected by Nanna. The DUB enzymes regulate ubiquitination in the ubiquitin-proteasome system (UPS). Dysregulation of DUB activity is implicated in many human diseases, highlighting their importance and promise for the development of novel therapeutics. Ubiquigent is the partner chosen by many leading industry and academic organisations for their drug discovery programmes in the fields of protein degradation, stabilisation and cellular signalling. Ubiquigent has an established specialised drug discovery platform and long-standing expertise in the exploitation of the DUBs for therapeutic benefit. The platform can be applied to support the development of DUB inhibitors, DUB-targeting PROTACs, and DUBTACs across any therapeutic area. Jason Mundin, CEO of Ubiquigent, commented: “We are delighted to enter this latest agreement and look forward to supporting the team at Nanna Therapeutics. Our platform was established to support those seeking to modulate DUB activity for therapeutic benefit and has been used by a long list of global partners which we are very pleased to add Nanna Therapeutics to.” To learn more about Ubiquigent’s discovery and development platform, please visit . View source version on businesswire.com: Contacts Esmé Walters Zyme Communications E-mail: esme.walters@zymecommunications.com Phone: +44 (0) 7377 543244 Source: Ubiquigent View this news release online at:

引进/卖出

100 项与 DUB inhibitor (Mission Therapeutics/Pfizer) 相关的药物交易

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