scholarly journals Targeting endogenous K-RAS for degradation through the affinity-directed protein missile system

2019 ◽  
Author(s):  
Sascha Röth ◽  
Thomas J. Macartney ◽  
Agnieszka Konopacka ◽  
Markus A. Queisser ◽  
Gopal P. Sapkota
Keyword(s):  
Clinical Trials ◽  
Drug Discovery ◽  
Specific Inhibitor ◽  
Ubiquitin Proteasome System ◽  
Ras Proteins ◽  
Alternative Therapeutic Approach ◽  
Ubiquitin Proteasome ◽  
Endogenous Proteins ◽  
Missile System ◽  
Ras Inhibitors

AbstractFor over three decades, K-RAS has been known as the holy grail of cancer targets, one of the most frequently mutated oncogenes in cancer. Because the development of conventional small molecule K-RAS inhibitors has been extremely challenging, K-RAS has been dubbed as an undruggable target, and only recently a mutation specific inhibitor has reached clinical trials. Targeted protein degradation has emerged as a new modality in drug discovery to tackle undruggable targets. However, no degrader for K-RAS has been described thus far. Our laboratory has developed an Affinity-directed PROtein Missile (AdPROM) system for targeted proteolysis of endogenous proteins through the ubiquitin proteasome system. Here, we show that we can achieve degradation of endogenous K-RAS and H-RAS in different cell lines in a targeted manner using our AdPROM system. Our findings imply that endogenous RAS proteins can be targeted for proteolysis, thereby offering tantalising possibilities for an alternative therapeutic approach to these so-called undruggable targets in cancer.

Improving Prospects for Targeting RAS

2015 ◽  
Vol 33 (31) ◽  
pp. 3650-3659 ◽  
Author(s):  
Harshabad Singh ◽  
Dan L. Longo ◽  
Bruce A. Chabner
Keyword(s):  
Clinical Trials ◽  
Structure Function ◽  
Solid Tumors ◽  
Therapeutic Interventions ◽  
Ras Proteins ◽  
Ras Mutations ◽  
Downstream Signaling ◽  
Synthetically Lethal ◽  
Intense Research ◽  
Ras Inhibitors

RAS mutations are among the most common oncogenic drivers in human cancers, affecting nearly a third of all solid tumors and around a fifth of common myeloid malignancies, but they have evaded therapeutic interventions, despite being the focus of intense research over the last three decades. Recent discoveries lend new understanding about the structure, function, and signaling of RAS and have opened new avenues for development of much needed new therapies. We discuss the various approaches under investigation to target mutant RAS proteins. The recent development of direct RAS inhibitors specific to KRAS G12C mutations represents a landmark discovery that promises to change the perception about RAS's druggability. Multiple clinical trials targeting synthetically lethal partners and/or downstream signaling partners of RAS are underway. Novel inhibitors targeting various arms of RAS processing and signaling have yielded encouraging results in the laboratory, but refinement of the drug-like properties of these molecules is required before they will be ready for the clinic.

scholarly journals UbiHub: a data hub for the explorers of ubiquitination pathways

2019 ◽  
Vol 35 (16) ◽  
pp. 2882-2884 ◽  
Author(s):  
Lihua Liu ◽  
David R Damerell ◽  
Leonidas Koukouflis ◽  
Yufeng Tong ◽  
Brian D Marsden ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Phylogenetic Trees ◽  
Ubiquitin Proteasome System ◽  
E3 Ligases ◽  
Protein Target ◽  
Protein Ubiquitination ◽  
Online Resource ◽  
Specific Protease ◽  
Ubiquitin Proteasome ◽  
Ubiquitin Specific Protease

Abstract Motivation Protein ubiquitination plays a central role in important cellular machineries such as protein degradation or chromatin-mediated signaling. With the recent discovery of the first potent ubiquitin-specific protease inhibitors, and the maturation of proteolysis targeting chimeras as promising chemical tools to exploit the ubiquitin-proteasome system, protein target classes associated with ubiquitination pathways are becoming the focus of intense drug-discovery efforts. Results We have developed UbiHub, an online resource that can be used to visualize a diverse array of biological, structural and chemical data on phylogenetic trees of human protein families involved in ubiquitination signaling, including E3 ligases and deubiquitinases. This interface can inform target prioritization and drug design, and serves as a navigation tool for medicinal chemists, structural and cell biologists exploring ubiquitination pathways. Availability and implementation https://ubihub.thesgc.org.

Drug discovery in the ubiquitin–proteasome system

2006 ◽  
Vol 5 (7) ◽  
pp. 596-613 ◽  
Author(s):  
Grzegorz Nalepa ◽  
Mark Rolfe ◽  
J. Wade Harper
Keyword(s):  
Drug Discovery ◽  
Ubiquitin Proteasome System ◽  
Ubiquitin Proteasome

The Present and Future of Novel Protein Degradation Technology

2019 ◽  
Vol 19 (20) ◽  
pp. 1784-1788 ◽  
Author(s):  
Liwen Xia ◽  
Wei Liu ◽  
Yinsen Song ◽  
Hailiang Zhu ◽  
Yongtao Duan
Keyword(s):  
Drug Discovery ◽  
Protein Degradation ◽  
Ubiquitin Proteasome System ◽  
Vital Role ◽  
Therapeutic Modality ◽  
Bifunctional Molecules ◽  
Subsequent Degradation ◽  
Ubiquitin Proteasome ◽  
Future Direction ◽  
Novel Protein

Proteolysis targeting chimeras (PROTACs), as a novel therapeutic modality, play a vital role in drug discovery. Each PROTAC contains three key parts; a protein-of-interest (POI) ligand, a E3 ligase ligand, and a linker. These bifunctional molecules could mediate the degradation of POIs by hijacking the activity of E3 ubiquitin ligases for POI ubiquitination and subsequent degradation via the ubiquitin proteasome system (UPS). With several advantages over other therapeutic strategies, PROTACs have set off a new upsurge of drug discovery in recent years. ENDTAC, as the development of PROTACs technology, is now receiving more attention. In this review, we aim to summarize the rapid progress from 2018 to 2019 in protein degradation and analyze the challenges and future direction that need to be addressed in order to efficiently develop potent protein degradation technology.

Progress in targeting RAS with small molecule drugs

2019 ◽  
Vol 476 (2) ◽  
pp. 365-374 ◽  
Author(s):  
Frank McCormick
Keyword(s):  
Clinical Trials ◽  
Drug Discovery ◽  
Small Molecules ◽  
Active Site ◽  
Biochemical Properties ◽  
Ras Proteins ◽  
Oncogenic Ras ◽  
Small Molecule Drugs ◽  
Related Proteins ◽  
Effector Binding

Abstract RAS proteins have traditionally been deemed undruggable, as they do not possess an active site to which small molecules could bind but small molecules that target one form of oncogenic RAS, KRAS G12C, are already in preclinical and clinical trials, and several other compounds that bind to different RAS proteins at distinct sites are in earlier stage evaluation. KRAS is the major clinical target, as it is by far the most significant form of RAS in terms of cancer incidence. Unfortunately, KRAS exists in two isoforms, each with unique biochemical properties. This complicates efforts to target KRAS specifically. KRAS is also a member of a family of closely related proteins, which share similar effector-binding regions and G-domains, further increasing the challenge of specificity. Nevertheless, progress is being made, driven by new drug discovery technologies and creative science.

Deregulation of the ubiquitin system and p53 proteolysis modify the apoptotic response in B-CLL lymphocytes

Blood ◽  
2000 ◽  
Vol 96 (1) ◽  
pp. 269-274 ◽  
Author(s):  
Peggy Masdehors ◽  
Hélène Merle-Béral ◽  
Karim Maloum ◽  
Satoshi Ömura ◽  
Henri Magdelénat ◽  
...  
Keyword(s):  
Specific Inhibitor ◽  
Ubiquitin Proteasome System ◽  
Lymphocytic Leukemia ◽  
Wild Type ◽  
Apoptotic Death ◽  
Ubiquitin System ◽  
Ubiquitin Proteasome ◽  
Increased Sensitivity ◽  
P53 Stability ◽  
Wild Type P53

We recently reported increased sensitivity of B-cell chronic lymphocytic leukemia (B-CLL) lymphocytes to apoptotic death activation by the proteasome-specific inhibitor lactacystin. Here, we show that only specific—not nonspecific—proteasomal inhibitors can discriminate between malignant and normal lymphocytes in inducing the apoptotic death response. Indeed, lactacystin and its active metaboliteclasto-lactacystin β-lactone induced apoptotic death in CLL but not in normal lymphocytes. This difference was completely abolished when tripeptide aldehydes such as MG132 or LLnL (which can also inhibit calpains) were used as less specific proteasomal inhibitors. Moreover, B-CLL cells exhibited a constitutive altered ubiquitin-proteasome system, including a threefold higher chymotrypsin-like proteasomal activity and high levels of nuclear ubiquitin-conjugated proteins compared with normal lymphocytes. Interestingly, B-CLL cells also displayed altered proteolytic regulation of wild-type p53, an apoptotic factor reported to be a substrate for the ubiquitin-proteasome system. Nuclear wild-type p53 accumulated after lactacystin treatment used at the discriminating concentration in malignant, but not in normal, lymphocytes. In contrast, p53 was stabilized by MG132 or LLnL in malignant and normal cells undergoing apoptosis, indicating that in normal lymphocytes p53 is regulated mainly by calpains and not by the ubiquitin-proteasome system. This work raises the possibility that two different proteolytic pathways controlling p53 stability may be pathologically imbalanced. This could result in modification of apoptosis control, since in CLL-lymphocytes a highly upregulated ubiquitin-proteasome system, which controls p53 stability among other apoptotic factors, was correlated with an increased propensity of these cells to apoptosis triggered by lactacystin.

scholarly journals Targeting Cullin–RING E3 ubiquitin ligases for drug discovery: structure, assembly and small-molecule modulation

2015 ◽  
Vol 467 (3) ◽  
pp. 365-386 ◽  
Author(s):  
Emil Bulatov ◽  
Alessio Ciulli
Keyword(s):  
Drug Discovery ◽  
Small Molecule ◽  
Ubiquitin Ligases ◽  
Ubiquitin Proteasome System ◽  
E3 Ubiquitin Ligases ◽  
Comprehensive Overview ◽  
Ubiquitin System ◽  
Ubiquitin Proteasome ◽  
New Gene ◽  
Structure Assembly

In the last decade, the ubiquitin–proteasome system has emerged as a valid target for the development of novel therapeutics. E3 ubiquitin ligases are particularly attractive targets because they confer substrate specificity on the ubiquitin system. CRLs [Cullin–RING (really interesting new gene) E3 ubiquitin ligases] draw particular attention, being the largest family of E3s. The CRLs assemble into functional multisubunit complexes using a repertoire of substrate receptors, adaptors, Cullin scaffolds and RING-box proteins. Drug discovery targeting CRLs is growing in importance due to mounting evidence pointing to significant roles of these enzymes in diverse biological processes and human diseases, including cancer, where CRLs and their substrates often function as tumour suppressors or oncogenes. In the present review, we provide an account of the assembly and structure of CRL complexes, and outline the current state of the field in terms of available knowledge of small-molecule inhibitors and modulators of CRL activity. A comprehensive overview of the reported crystal structures of CRL subunits, components and full-size complexes, alone or with bound small molecules and substrate peptides, is included. This information is providing increasing opportunities to aid the rational structure-based design of chemical probes and potential small-molecule therapeutics targeting CRLs.

scholarly journals PROTAC: An Effective Targeted Protein Degradation Strategy for Cancer Therapy

2021 ◽  
Vol 12 ◽  
Author(s):  
Si-Min Qi ◽  
Jinyun Dong ◽  
Zhi-Yuan Xu ◽  
Xiang-Dong Cheng ◽  
Wei-Dong Zhang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Clinical Trials ◽  
Protein Degradation ◽  
Ubiquitin Proteasome System ◽  
Breast Cancer Treatment ◽  
E3 Ligases ◽  
Target Proteins ◽  
Endogenous Protein ◽  
Ubiquitin Proteasome ◽  
Insight Into

Proteolysis targeting chimeric (PROTAC) technology is an effective endogenous protein degradation tool developed in recent years that can ubiquitinate the target proteins through the ubiquitin-proteasome system (UPS) to achieve an effect on tumor growth. A number of literature studies on PROTAC technology have proved an insight into the feasibility of PROTAC technology to degrade target proteins. Additionally, the first oral PROTACs (ARV-110 and ARV-471) have shown encouraging results in clinical trials for prostate and breast cancer treatment, which inspires a greater enthusiasm for PROTAC research. Here we focus on the structures and mechanisms of PROTACs and describe several classes of effective PROTAC degraders based on E3 ligases.

Sign in / Sign up

Export Citation Format

Share Document