Development of Highly Potent, Selective, and Cellular Active Triazolo[1,5- a]pyrimidine-Based Inhibitors Targeting the DCN1-UBC12 Protein-Protein Interaction

Journal of Medicinal Chemistry
Shuai WangHong-Min Liu

Abstract

The cullin-RING ubiquitin ligases (CRLs) are responsible for about 20% of cellular protein degradation and regulate diverse cellular processes, and the dysfunction of CRLs is implicated in human diseases. Targeting the CRLs has become an emerging strategy for the treatment of human diseases. Herein, we describe the discovery of a hit compound from our in-house library and further structure-based optimizations, which have enabled the identification of new triazolo[1,5- a]pyrimidine-based inhibitors targeting the DCN1-UBC12 interaction. Compound WS-383 blocks the DCN1-UBC12 interaction (IC50 = 11 nM) reversibly and shows selectivity over selected kinases. WS-383 exhibits cellular target engagement to DCN1 in MGC-803 cells. WS-383 inhibits Cul3/1 neddylation selectively over other cullins and also induces accumulation of p21, p27, and NRF2. Collectively, targeting the DCN1-UBC12 interaction would be a viable strategy for selective neddylation inhibition of Cul3/1 and may be of therapeutic potential for disease treatment in which Cul3/1 is dysregulated.

References

Nov 13, 1999·Nature Cell Biology·A C CarranoM Pagano
Apr 25, 2000·Biochemical and Biophysical Research Communications·M MorimotoH Yasuda
Feb 3, 2005·Nature Reviews. Molecular Cell Biology·Matthew D Petroski, Raymond J Deshaies
Jan 22, 2008·Molecular Cell·Thimo KurzFrank Sicheri
Apr 11, 2009·Nature·Teresa A SoucySteven P Langston
Jun 11, 2009·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Teresa A SoucyMark Rolfe
Jun 23, 2009·Toxicology and Applied Pharmacology·Suryakant K NitureAnil K Jaiswal
Jun 22, 2010·Neoplasia : an International Journal for Oncology Research·Stephen R BroderickBhuvanesh Singh
Jan 12, 2011·Sub-cellular Biochemistry·Raymond J DeshaiesAnjanabha Saha
Jan 18, 2011·Chemical Communications : Chem Comm·Chung-Hang LeungDik-Lung Ma
Aug 5, 2011·The Journal of Biological Chemistry·Kenneth WuZhen-Qiang Pan
Apr 14, 2012·Cancer Research and Treatment : Official Journal of Korean Cancer Association·Jinyoung YooChang-Suk Kang
Nov 16, 2012·Current Pharmaceutical Design·Yongchao Zhao, Yi Sun
Nov 28, 2012·PloS One·Hai-Jing ZhongDik-Lung Ma
Sep 12, 2013·Redox Biology·Ana Cristina Andérica-RomeroJosé Pedraza-Chaverri
Jan 15, 2014·Antioxidants & Redox Signaling·Yongchao ZhaoYi Sun
May 23, 2014·Journal of Chemical Information and Modeling·Rashmi KumariAndrew Lynn
May 27, 2014·Journal of Chemical Information and Modeling·Shengping ZhangYisheng Lai
Dec 23, 2014·Nature Reviews. Molecular Cell Biology·Radoslav I EnchevMatthias Peter
Jul 27, 2015·Drug Discovery Today·Peng WuMads H Clausen
May 21, 2016·Frontiers in Oncology·Hsin-Yi Chen, Ruey-Hwa Chen
Oct 25, 2016·Nature Communications·Anita SchlierfBruno Martoglio
Jun 6, 2017·Nature Chemical Biology·Daniel C ScottR Kip Guy
Nov 13, 2017·Biochimica Et Biophysica Acta. Reviews on Cancer·Ji ChengWenyi Wei
Feb 14, 2018·Journal of Medicinal Chemistry·Haibin ZhouShaomeng Wang
Mar 17, 2018·Journal of Medicinal Chemistry·Jared T HammillR Kiplin Guy

❮ Previous
Next ❯

Citations

Nov 2, 2019·Future Medicinal Chemistry·Yuan FangHong-Min Liu
Nov 25, 2020·Bioorganic & Medicinal Chemistry·Shu-Yu WangSai-Yang Zhang
Jan 2, 2021·European Journal of Medicinal Chemistry·Jin-Ling HuoHong-Min Liu
Feb 19, 2021·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Qianqian SongHong-Min Liu
Mar 24, 2021·European Journal of Medicinal Chemistry·Wenjuan ZhouWen Zhao
Apr 9, 2021·Journal of Hematology & Oncology·Yi-Chao ZhengHong-Min Liu
Apr 27, 2021·Frontiers in Cell and Developmental Biology·Wenbin GaiHong Jiang
Aug 30, 2019·Journal of Medicinal Chemistry·Ho Shin KimR Kiplin Guy
Aug 30, 2021·European Journal of Medicinal Chemistry·Jian SongSai-Yang Zhang

❮ Previous
Next ❯

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.