BIOMAT Database Logo BIOMAT Database Logo

Optimisation of pyrazolo[1,5-a]pyrimidin-7(4H)-one derivatives as novel Hsp90 C-terminal domain inhibitors against Ewing sarcoma. 2023

Živa Zajec, and Jaka Dernovšek, and Martin Distel, and Martina Gobec, and Tihomir Tomašič
University of Ljubljana, Faculty of Pharmacy, Aškerčeva cesta 7, 1000 Ljubljana, Slovenia.

Ewing sarcoma is the second most prevalent paediatric malignant bone tumour. In most cases, it is driven by the fusion oncoprotein EWS::FLI1, which acts as an aberrant transcription factor and dysregulates gene expression. EWS::FLI1 and a large number of downstream dysregulated proteins are Hsp90 client proteins, making Hsp90 an attractive target for the treatment of Ewing sarcoma. In this article, we report a new structural class of allosteric Hsp90 C-terminal domain (CTD) inhibitors based on the virtual screening hit TVS24, which showed antiproliferative activity in the SK-N-MC Ewing sarcoma cell line with an IC50 value of 15.9 ± 0.7 µM. The optimised compounds showed enhanced anticancer activity in the SK-N-MC cell line. Exposure of Ewing sarcoma cells to the most potent analogue 11c resulted in depletion of critical Hsp90 client proteins involved in cancer pathways such as EWS::FLI1, CDK4, RAF-1 and IGF1R, without inducing a heat shock response. The results of this study highlight Hsp90 CTD inhibitors as promising new agents for the treatment of Ewing sarcoma.

UI MeSH Term Description Entries
D001859 Bone Neoplasms Tumors or cancer located in bone tissue or specific BONES. Bone Cancer,Cancer of Bone,Cancer of the Bone,Neoplasms, Bone,Bone Neoplasm,Neoplasm, Bone
D002648 Child A person 6 to 12 years of age. An individual 2 to 5 years old is CHILD, PRESCHOOL. Children
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000970 Antineoplastic Agents Substances that inhibit or prevent the proliferation of NEOPLASMS. Anticancer Agent,Antineoplastic,Antineoplastic Agent,Antineoplastic Drug,Antitumor Agent,Antitumor Drug,Cancer Chemotherapy Agent,Cancer Chemotherapy Drug,Anticancer Agents,Antineoplastic Drugs,Antineoplastics,Antitumor Agents,Antitumor Drugs,Cancer Chemotherapy Agents,Cancer Chemotherapy Drugs,Chemotherapeutic Anticancer Agents,Chemotherapeutic Anticancer Drug,Agent, Anticancer,Agent, Antineoplastic,Agent, Antitumor,Agent, Cancer Chemotherapy,Agents, Anticancer,Agents, Antineoplastic,Agents, Antitumor,Agents, Cancer Chemotherapy,Agents, Chemotherapeutic Anticancer,Chemotherapy Agent, Cancer,Chemotherapy Agents, Cancer,Chemotherapy Drug, Cancer,Chemotherapy Drugs, Cancer,Drug, Antineoplastic,Drug, Antitumor,Drug, Cancer Chemotherapy,Drug, Chemotherapeutic Anticancer,Drugs, Antineoplastic,Drugs, Antitumor,Drugs, Cancer Chemotherapy
D012512 Sarcoma, Ewing A malignant tumor of the bone which always arises in the medullary tissue, occurring more often in cylindrical bones. The tumor occurs usually before the age of 20, about twice as frequently in males as in females. Ewing's Tumor,Sarcoma, Ewing's,Ewing Sarcoma,Ewing Tumor,Ewing's Sarcoma,Ewings Sarcoma,Ewings Tumor,Sarcoma, Ewings,Tumor, Ewing,Tumor, Ewing's
D045744 Cell Line, Tumor A cell line derived from cultured tumor cells. Tumor Cell Line,Cell Lines, Tumor,Line, Tumor Cell,Lines, Tumor Cell,Tumor Cell Lines

Related Publications

Živa Zajec, and Jaka Dernovšek, and Martin Distel, and Martina Gobec, and Tihomir Tomašič
Activation of KCNQ2/3 potassium channels by novel pyrazolo[1,5-a]pyrimidin-7(4H)-one derivatives.
January 2011, Pharmacology,
Živa Zajec, and Jaka Dernovšek, and Martin Distel, and Martina Gobec, and Tihomir Tomašič
Discovery of 4H-pyrazolo[1,5-a]pyrimidin-7-ones as potent inhibitors of hepatitis C virus polymerase.
September 2009, Bioorganic & medicinal chemistry letters,
Živa Zajec, and Jaka Dernovšek, and Martin Distel, and Martina Gobec, and Tihomir Tomašič
Synthesis and pharmacological evaluation of pyrazolo[1,5-a]pyrimidin-7(4H)-one derivatives as potential GABAA-R ligands.
March 2017, Bioorganic & medicinal chemistry,
Živa Zajec, and Jaka Dernovšek, and Martin Distel, and Martina Gobec, and Tihomir Tomašič
Surrogating and redirection of pyrazolo[1,5-a]pyrimidin-7(4H)-one core, a novel class of potent and selective DPP-4 inhibitors.
February 2018, Bioorganic & medicinal chemistry,
Živa Zajec, and Jaka Dernovšek, and Martin Distel, and Martina Gobec, and Tihomir Tomašič
Structure-Activity Relationships of Pyrazolo[1,5-a]pyrimidin-7(4H)-ones as Antitubercular Agents.
February 2021, ACS infectious diseases,
Živa Zajec, and Jaka Dernovšek, and Martin Distel, and Martina Gobec, and Tihomir Tomašič
Modulation of K(v)7 potassium channels by a novel opener pyrazolo[1,5-a]pyrimidin-7(4H)-one compound QO-58.
February 2013, British journal of pharmacology,
Živa Zajec, and Jaka Dernovšek, and Martin Distel, and Martina Gobec, and Tihomir Tomašič
Synthesis and in vitro anti-epileptic activities of novel [1,2,4]-triazolo[1,5-a]pyrimidin-7(4H)-one derivatives.
December 2019, Journal of Asian natural products research,
Živa Zajec, and Jaka Dernovšek, and Martin Distel, and Martina Gobec, and Tihomir Tomašič
Design, synthesis and biological activity of pyrazolo[1,5-a]pyrimidin-7(4H)-ones as novel Kv7/KCNQ potassium channel activators.
March 2011, European journal of medicinal chemistry,
Živa Zajec, and Jaka Dernovšek, and Martin Distel, and Martina Gobec, and Tihomir Tomašič
Synthesis of 5,6-dihydro-4H-benzo[d]isoxazol-7-one and 5,6-dihydro-4H-isoxazolo[5,4-c]pyridin-7-one derivatives as potential Hsp90 inhibitors.
November 2015, Chemical biology & drug design,
Živa Zajec, and Jaka Dernovšek, and Martin Distel, and Martina Gobec, and Tihomir Tomašič
Efficient microwave-assisted Suzuki-Miyaura cross-coupling reaction of 3-bromo pyrazolo[1,5-a]pyrimidin-5(4H)-one: towards a new access to 3,5-diarylated 7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine derivatives.
January 2021, RSC advances,
Copied contents to your clipboard!