Targeting deubiquitinating enzymes (DUBs) has emerged as a promising therapeutic approach in several human cancers and other diseases. DUB inhibitors are exciting pharmacological tools but often ...exhibit limited cellular potency. Here we report PROTACs based on a ubiquitin-specific protease 7 (USP7) inhibitor scaffold to degrade USP7. By investigating several linker and E3 ligand types, including novel cereblon recruiters, we discovered a highly selective USP7 degrader tool compound that induced apoptosis of USP7-dependent cancer cells. This work represents one of the first DUB degraders and unlocks a new drug target class for protein degradation.
A novel class of USP7 PROTACs were designed and synthesized. CST967, a CRBN-based degrader, showed potent and selective depletion of USP7 leading to apoptosis in multiple cancer lines.
Bacterial resistance is an increasing threat to healthcare systems, highlighting the need for discovering new antibacterial agents. An established technique, fragment-based drug discovery, was used ...to target a bacterial enzyme Ddl involved in the biosynthesis of peptidoglycan. We assembled general and focused fragment libraries that were screened in a biochemical inhibition assay. Screening revealed a new fragment-hit inhibitor of DdlB with a Ki value of 20.7 ± 4.5 µM. Binding to the enzyme was confirmed by an orthogonal biophysical method, surface plasmon resonance, making the hit a promising starting point for fragment development.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
The establishment of the Young Scientists Network (YSN) by the European Federation for Medicinal Chemistry (EFMC) served as a proactive response to the evolving landscape of the scientific community. ...The YSN aims to assist early‐career medicinal chemists and chemical biologists by responding to emerging themes, such as the influence of social media, shifts in gender balance within the scientific population, and evolving educational opportunities. The YSN also ensures that the upcoming generation of scientists actively contributes to shape the EFMC's strategic direction while addressing their specific needs. Initially conceived as a general concept, YSN has evolved into a proactive and dynamic team which demonstrates a tangible impact. To boost the impact of the YSN and involve additional motivated young scientists, we have adopted a novel organization, and structured the team in seven working groups (WGs). Herein, we will discuss the tasks of the different WGs as well as the activities planned for the near future. We believe this structure will strengthen the pivotal role YSN has already played in serving medicinal chemists and chemical biologists in Europe. The YSN now has the structure and motivation to pave the way to attract young scientists across Europe and to give them the stage within EFMC.
A step forward in YSN organization: The Young Scientists Network (YSN) of the EFMC plays a pivotal role in shaping the Medicinal Chemistry and Chemical Biology landscape for early‐career scientists across Europe. The activities of the YSN span from networking to training, including several prizes which recognise the achievements of young scientists. The novel YSN organization aims to boost the reach and impact of the YSN in order to provide new opportunities and a successful future for our community.
The immunoproteasome is a multicatalytic protease that is predominantly expressed in cells of hematopoietic origin. Its elevated expression has been associated with autoimmune diseases, various types ...of cancer, and inflammatory diseases. Selective inhibition of its catalytic activities is therefore a viable approach for the treatment of these diseases. However, the development of immunoproteasome-selective inhibitors with non-peptidic scaffolds remains a challenging task. We previously reported 7
-furo3,2-
chromen-7-one (psoralen)-based compounds with an oxathiazolone warhead as selective inhibitors of the chymotrypsin-like (β5i) subunit of immunoproteasome. Here, we describe the influence of the electrophilic warhead variations at position 3 of the psoralen core on the inhibitory potencies. Despite mapping the chemical space with different warheads, all compounds showed decreased inhibition of the β5i subunit of immunoproteasome in comparison to the parent oxathiazolone-based compound. Although suboptimal, these results provide crucial information about structure-activity relationships that will serve as guidance for the further design of (immuno)proteasome inhibitors.
Naturally occurring compounds represent a vast pool of pharmacologically active entities. One of such compounds is andrographolide, which is endowed with many beneficial properties, including the ...activity against severe acute respiratory syndrome coronavirus type 2 (SARS‐CoV‐2). To initiate a drug repurposing or hit optimization campaign, it is imperative to unravel the primary mechanism(s) of the antiviral action of andrographolide. Here, we showed by means of a reporter gene assay that andrographolide exerts its anti‐SARS‐CoV‐2 effects by inhibiting the interaction between Kelch‐like ECH‐associated protein 1 (KEAP1) and nuclear factor erythroid 2‐related factor 2 (NRF2) causing NRF2 upregulation. Moreover, we demonstrated that subtle structural modifications of andrographolide could lead to derivatives with stronger on‐target activities and improved physicochemical properties. Our results indicate that further optimization of this structural class is warranted to develop novel COVID‐19 therapies.
Synthetic andrographolide derivatives were synthesized and found to be potent activators of the KEAP1/NRF2 pathway and inhibitors of SARS‐CoV‐2 replication. Our Medicinal Chemistry efforts yielded highly selective NRF2 activators that are also accessible for the synthesis of tailored semisynthetic drugs or functional molecules.
Large-scale virtual screening of boronic acid derivatives was performed to identify nonpeptidic covalent inhibitors of the β5i subunit of the immunoproteasome. A hierarchical virtual screening ...cascade including noncovalent and covalent docking steps was applied to a virtual library of over 104,000 compounds. Then, 32 virtual hits were selected, out of which five were experimentally confirmed. Biophysical and biochemical tests showed micromolar binding affinity and time-dependent inhibitory potency for two compounds. These results validate the computational protocol that allows the screening of large compound collections. One of the lead-like boronic acid derivatives identified as a covalent immunoproteasome inhibitor is a suitable starting point for chemical optimization.
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•Computational screening yielded 44 new viscosity-reducing agents on two model mAbs.•Dual excipients for viscosity reduction and solution buffering were discovered.•Compounds with ...three or more charges reduce the viscosity of model mAb formulations.•Filtering based on physicochemical properties can be applied to other mAb formulations.
For the development of concentrated monoclonal antibody formulations for subcutaneous administration, the main challenge is the high viscosity of the solutions. To compensate for this, viscosity reducing agents are commonly used as excipients. Here, we applied two computational chemistry approaches to discover new viscosity-reducing agents: fingerprint similarity searching, and physicochemical property filtering. In total, 94 compounds were selected and experimentally evaluated on two model monoclonal antibodies, which led to the discovery of 44 new viscosity-reducing agents. Analysis of the results showed that using a simple filter that selects only compounds with three or more charge groups is a good ‘rule of thumb’ for selecting potential viscosity-reducing agents for two model monoclonal antibody formulations.
Various BRAF kinase inhibitors were developed to treat cancers carrying the BRAF
V600E
mutation. First-generation BRAF inhibitors could lead to paradoxical activation of the MAPK pathway, limiting ...their clinical usefulness. Here, we show the development of two series of BRAF
V600E
-targeting PROTACs and demonstrate that the exchange of the inhibitor scaffold from vemurafenib to paradox-breaker ligands resulted in BRAF
V600E
degraders that did not cause paradoxical ERK activation.
Novel BRAF
V600E
PROTACs were developed that maintain target degradation while sparing paradoxical activation of the MAPK pathway in BRAF
wt
cells.
We present a state-of-the-art virtual screening workflow aiming at the identification of novel CC chemokine receptor 7 (CCR7) antagonists. Although CCR7 is associated with a variety of human ...diseases, such as immunological disorders, inflammatory diseases, and cancer, this target is underexplored in drug discovery and there are no potent and selective CCR7 small molecule antagonists available today. Therefore, computer-aided ligand-based, structure-based, and joint virtual screening campaigns were performed. Hits from these virtual screenings were tested in a CCL19-induced calcium signaling assay. After careful evaluation, none of the
hits were confirmed to have an antagonistic effect on CCR7. Hence, we report here a valuable set of 287 inactive compounds that can be used as experimentally validated decoys.
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•BacA is an important conserved bacterial protein and a promising drug target.•We identified the first small molecule inhibitors of BacA via ensemble docking.•Novel inhibitors possess ...5-sulfamoyl-2-thenoic acid scaffold.•Hit compounds display IC50s from 42 to 374 μM and antibacterial activity on E. coli.•Reported compounds are a valuable starting point for new antibacterial drug design.
Increasing resistance to common antibiotics is becoming a major challenge that requires the development of new antibacterial agents. Peptidoglycan is an essential heteropolymer of the bacterial envelope that ensures the integrity and shape of all bacteria and is also an important target for antibiotics. The biosynthesis of peptidoglycan depends on a lipid carrier, undecaprenyl phosphate. As a byproduct of peptidoglycan polymerization, the lipid carrier is released as undecaprenyl pyrophosphate, which must be recycled to allow new polymerization cycles. To this end, it undergoes a dephosphorylation process catalyzed by the membrane phosphatase BacA, which is specific and highly conserved in bacteria. In the present study, we identified small molecules displaying inhibitory potency towards BacA. We began by preparing a commercial compound library, followed by high-throughput virtual screening by ensemble docking using the 3D structure of BacA and molecular dynamics snapshots to account for the flexibility of the protein. Of 83 compounds computationally selected and tested in a biochemical assay, one sulfamoylthiophene molecule showed significant inhibition of the undecaprenyl pyrophosphate dephosphorylation activity catalyzed by BacA. Subsequently, an additional 33 scaffold analogs were selected and acquired, of which 6 compounds exhibited BacA inhibition. The IC50 values of these compounds ranged from 42 to 366 μM. In addition, significant antibacterial activity against Escherichia coli was observed in TolC/PAP2-depleted strains. We believe that the overall strategy followed in this study and the identified class of inhibitors provide a solid foundation for the further development of potent BacA-targeted inhibitors and the discovery of novel antibacterial compounds.
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