Project information
Development of new MUS81 nuclease inhibitors as chemical biology probe with clinical progression
- Project Identification
- MUNI/M/1894/2014
- Project Period
- 3/2015 - 12/2017
- Investor / Pogramme / Project type
-
Masaryk University
- Grant Agency of Masaryk University
- INTERDISCIPLINARY - Interdisciplinary research projects
- MU Faculty or unit
-
Faculty of Medicine
- doc. Mgr. Lumír Krejčí, Ph.D.
- Rakesh Aithal, Ph.D., M.Sc.
- Mgr. Veronika Altmannová, Ph.D.
- Mgr. María Victoria Marini Palomeque, Ph.D.
- RNDr. Petra Matulová, CSc.
- Fedor Nikulenkov, Ph.D.
- Pounami Samadder, Ph.D.
- RNDr. Mário Špírek, PhD.
- Other MU Faculty/Unit
-
Faculty of Science
- doc. Mgr. Kamil Paruch, Ph.D.
- Mgr. Lenka Černová
- Mgr. Štěpán Havel
- PrashantKumar Khirsariya, Ph.D., M.Sc.
- Mgr. Michal Poljak
- Other MU Faculty/Unit
- Faculty of Informatics
- Other MU Faculty/Unit
-
Central European Institute of Technology
- doc. Mgr. Martin Trbušek, Dr.
- Mgr. Jana Zemanová, Ph.D.
The proposed research is envisioned to yield new small-molecule inhibitors of human MUS81 endonuclease. MUS81 plays critical role in resolution of late replication and recombination intermediates essential for proper segregation of chromosomes during mitosis. Its absence leads to accumulation of anaphase bridges, chromosomal breaks and fusions. Recent literature indicates that MUS81 represents a very promising target for pharmacological intervention, especially in the area of new anticancer therapies. It should be noted that until 2014, no crystal structure of human MUS81 was known. This, together with the fact that no small-molecule inhibitors of MUS81 have been reported yet, presents an excellent starting point for academic high-risk/high-gain project. This project represents unique interdisciplinary approach for proper medicinal chemistry optimization of our proprietary hit (compound 1B) together with its extensive in vitro and in vivo characterization. Furthermore, we will identify synthetic lethal partners for MUS81 deficiency with primary focus on clinically relevant genes. This together should lead to advanced leads that will be suitable for further preclinical (and possibly clinical) progression.
Publications
Total number of publications: 12
2018
-
Pyrazolotriazines as inhibitors of nucleases
Publisher: Japan Patent Office, state: Japan, patent's number: JP 6313906, year: 2018
-
Pyrazolotriazines as inhibitors of nucleases
Publisher: USPTO, state: United States of America, patent's number: US 9969741 B2, year: 2018
2017
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Esc2 promotes Mus81 complex-activity via its SUMO-like and DNA binding domains
Nucleic Acids Research, year: 2017, volume: 45, edition: 1, DOI
-
Fanconi-Anemia-Associated Mutations Destabilize RAD51 Filaments and Impair Replication Fork Protection
Cell Reports, year: 2017, volume: 21, edition: 2, DOI
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RECQ5 Helicase Cooperates with MUS81 Endonuclease in Processing Stalled Replication Forks at Common Fragile Sites during Mitosis
Molecular Cell, year: 2017, volume: 66, edition: 5, DOI
-
Role of PCNA and RFC in promoting Mus81-complex activity
BMC BIOLOGY, year: 2017, volume: 15, edition: 90, DOI
2016
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Cancer TARGETases: DSB Repair as a Pharmacological Target
Pharmacology & Therapeutics, year: 2016, volume: 161, edition: "May", DOI
-
DNA, the central molecule of aging
Mutation Research / Fundamental and Molecular Mechanisms of Mutagenesis, year: 2016, volume: 786, edition: "April", DOI
-
Mitochondrial dysfunction in DDR-related cancer predisposition syndromes
Biochimica et Biophysica Acta - Reviews on Cancer, year: 2016, volume: 1865, edition: 2, DOI
-
Pro-recombination Role of Srs2 Protein Requires SUMO (Small ubiquitin-like Modifier) but Is Independent of PCNA (Proliferating Cell Nuclear Antigen) Interaction
Journal of Biological Chemistry, year: 2016, volume: 291, edition: 14, DOI