Recent progress in small-molecule inhibitors for critical therapeutic targets of necroptosis

Nonapoptotic types of regulated cell death have attracted widespread interest since the discovery that certain forms of cell necrosis can be regulated. In particular, research into cell necroptosis has made significant progress in connection with kidney, inflammatory, degenerative and neoplastic diseases. Inhibitors targeting the critical necroptosis-associated proteins RIPK1/3 and MLKL have been in development for more than a decade. Herein the authors compile a list of the known small-molecule inhibitors of these enzymes and representative structures of compounds co-crystallized with these proteins and put forward some thoughts regarding their future development.

Download Full-text

Small-Molecule Inhibitors of the Programmed Cell Death-1/Programmed Death-Ligand 1 (PD-1/PD-L1) Interaction via Transiently Induced Protein States and Dimerization of PD-L1

Journal of Medicinal Chemistry ◽

10.1021/acs.jmedchem.7b00293 ◽

2017 ◽

Vol 60 (13) ◽

pp. 5857-5867 ◽

Cited By ~ 86

Author(s):

Katarzyna Guzik ◽

Krzysztof M. Zak ◽

Przemyslaw Grudnik ◽

Katarzyna Magiera ◽

Bogdan Musielak ◽

...

Keyword(s):

Cell Death ◽

Programmed Cell Death ◽

Small Molecule ◽

Small Molecule Inhibitors ◽

Programmed Death Ligand 1 ◽

Programmed Death ◽

Programmed Cell Death 1

Download Full-text

Targeting regulated cell death (RCD) with small-molecule compounds in cancer therapy: a revisited review of apoptosis, autophagy-dependent cell death and necroptosis

Drug Discovery Today ◽

10.1016/j.drudis.2021.10.011 ◽

2021 ◽

Author(s):

Wei Liu ◽

Wenke Jin ◽

Shiou Zhu ◽

Yi Chen ◽

Bo Liu

Keyword(s):

Cell Death ◽

Cancer Therapy ◽

Small Molecule ◽

Regulated Cell Death ◽

Dependent Cell

Download Full-text

Discovery of quinazoline derivatives as novel small-molecule inhibitors targeting the programmed cell death-1/programmed cell death-ligand 1 (PD-1/PD-L1) interaction

European Journal of Medicinal Chemistry ◽

10.1016/j.ejmech.2021.113998 ◽

2021 ◽

pp. 113998

Author(s):

Yu Wang ◽

Kun huang ◽

Yali Gao ◽

Dandan Yuan ◽

Lin Ling ◽

...

Keyword(s):

Cell Death ◽

Programmed Cell Death ◽

Small Molecule ◽

Small Molecule Inhibitors ◽

Programmed Cell Death 1 ◽

Quinazoline Derivatives

Download Full-text

Cell Death: Biological Mechanisms and Small Molecule Inhibitors

Wiley Encyclopedia of Chemical Biology ◽

10.1002/9780470048672.wecb059 ◽

2008 ◽

Author(s):

Olga Korkina ◽

Alexei Degterev

Keyword(s):

Cell Death ◽

Small Molecule ◽

Small Molecule Inhibitors ◽

Biological Mechanisms

Download Full-text

A phenolic small molecule inhibitor of RNase L prevents cell death from ADAR1 deficiency

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2006883117 ◽

2020 ◽

Vol 117 (40) ◽

pp. 24802-24812 ◽

Cited By ~ 1

Author(s):

Salima Daou ◽

Manisha Talukdar ◽

Jinle Tang ◽

Beihua Dong ◽

Shuvojit Banerjee ◽

...

Keyword(s):

Cell Death ◽

Protein Kinase ◽

Small Molecule ◽

Small Molecule Inhibitors ◽

Therapeutic Potential ◽

Protein Kinase Inhibitors ◽

Response To Treatment ◽

Rnase L ◽

Oligoadenylate Synthetase ◽

In Cells

The oligoadenylate synthetase (OAS)–RNase L system is an IFN-inducible antiviral pathway activated by viral infection. Viral double-stranded (ds) RNA activates OAS isoforms that synthesize the second messenger 2-5A, which binds and activates the pseudokinase-endoribonuclease RNase L. In cells, OAS activation is tamped down by ADAR1, an adenosine deaminase that destabilizes dsRNA. Mutation of ADAR1 is one cause of Aicardi-Goutières syndrome (AGS), an interferonopathy in children. ADAR1 deficiency in human cells can lead to RNase L activation and subsequent cell death. To evaluate RNase L as a possible therapeutic target for AGS, we sought to identify small-molecule inhibitors of RNase L. A 500-compound library of protein kinase inhibitors was screened for modulators of RNase L activity in vitro. We identified ellagic acid (EA) as a hit with 10-fold higher selectivity against RNase L compared with its nearest paralog, IRE1. SAR analysis identified valoneic acid dilactone (VAL) as a superior inhibitor of RNase L, with 100-fold selectivity over IRE1. Mechanism-of-action analysis indicated that EA and VAL do not bind to the pseudokinase domain of RNase L despite acting as ATP competitive inhibitors of the protein kinase CK2. VAL is nontoxic and functional in cells, although with a 1,000-fold decrease in potency, as measured by RNA cleavage activity in response to treatment with dsRNA activator or by rescue of cell lethality resulting from self dsRNA induced by ADAR1 deficiency. These studies lay the foundation for understanding novel modes of regulating RNase L function using small-molecule inhibitors and avenues of therapeutic potential.

Download Full-text

PD-1-Targeted Discovery of Peptide Inhibitors by Virtual Screening, Molecular Dynamics Simulation, and Surface Plasmon Resonance

Molecules ◽

10.3390/molecules24203784 ◽

2019 ◽

Vol 24 (20) ◽

pp. 3784 ◽

Cited By ~ 2

Author(s):

Yuanqiang Wang ◽

Haiqiong Guo ◽

Zhiwei Feng ◽

Siyi Wang ◽

Yuxuan Wang ◽

...

Keyword(s):

Molecular Dynamics ◽

Cell Death ◽

Surface Plasmon Resonance ◽

Virtual Screening ◽

Programmed Cell Death ◽

Surface Plasmon ◽

Small Molecule ◽

Plasmon Resonance ◽

Small Molecule Inhibitors ◽

Dynamics Simulation

The blockade of the programmed cell death protein 1/programmed cell death ligand 1 (PD-1/PD-L1) pathway plays a critical role in cancer immunotherapy by reducing the immune escape. Five monoclonal antibodies that antagonized PD-1/PD-L1 interaction have been approved by the Food and Drug Administration (FDA) and marketed as immunotherapy for cancer treatment. However, some weaknesses of antibodies, such as high cost, low stability, poor amenability for oral administration, and immunogenicity, should not be overlooked. To overcome these disadvantages, small-molecule inhibitors targeting PD-L1 were developed. In the present work, we applied in silico and in vitro approaches to develop short peptides targeting PD-1 as chemical probes for the inhibition of PD-1–PD-L1 interaction. We first predicted the potential binding pocket on PD-1/PD-L1 protein–protein interface (PPI). Sequentially, we carried out virtual screening against our in-house peptide library to identify potential ligands. WANG-003, WANG-004, and WANG-005, three of our in-house peptides, were predicted to bind to PD-1 with promising docking scores. Next, we conducted molecular docking and molecular dynamics (MD) simulation for the further analysis of interactions between our peptides and PD-1. Finally, we evaluated the affinity between peptides and PD-1 by surface plasmon resonance (SPR) binding technology. The present study provides a new perspective for the development of PD-1 inhibitors that disrupt PD-1–PD-L1 interactions. These promising peptides have the potential to be utilized as a novel chemical probe for further studies, as well as providing a foundation for further designs of potent small-molecule inhibitors targeting PD-1.

Download Full-text