The Importance of the Pyrazole Scaffold in the Design of Protein Kinases Inhibitors as Targeted Anticancer Therapies
The altered activation or overexpression of protein kinases (PKs) is a major subject of research in oncology and their inhibition using small molecules, protein kinases inhibitors (PKI) is the best available option for the cure of cancer. The pyrazole ring is extensively employed in the field of med...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-07-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/28/14/5359 |
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| author | George Mihai Nitulescu Gheorghe Stancov Oana Cristina Seremet Georgiana Nitulescu Dragos Paul Mihai Cosmina Gabriela Duta-Bratu Stefania Felicia Barbuceanu Octavian Tudorel Olaru |
| author_facet | George Mihai Nitulescu Gheorghe Stancov Oana Cristina Seremet Georgiana Nitulescu Dragos Paul Mihai Cosmina Gabriela Duta-Bratu Stefania Felicia Barbuceanu Octavian Tudorel Olaru |
| author_sort | George Mihai Nitulescu |
| collection | DOAJ |
| description | The altered activation or overexpression of protein kinases (PKs) is a major subject of research in oncology and their inhibition using small molecules, protein kinases inhibitors (PKI) is the best available option for the cure of cancer. The pyrazole ring is extensively employed in the field of medicinal chemistry and drug development strategies, playing a vital role as a fundamental framework in the structure of various PKIs. This scaffold holds major importance and is considered a privileged structure based on its synthetic accessibility, drug-like properties, and its versatile bioisosteric replacement function. It has proven to play a key role in many PKI, such as the inhibitors of Akt, Aurora kinases, MAPK, B-raf, JAK, Bcr-Abl, c-Met, PDGFR, FGFRT, and RET. Of the 74 small molecule PKI approved by the US FDA, 8 contain a pyrazole ring: Avapritinib, Asciminib, Crizotinib, Encorafenib, Erdafitinib, Pralsetinib, Pirtobrutinib, and Ruxolitinib. The focus of this review is on the importance of the unfused pyrazole ring within the clinically tested PKI and on the additional required elements of their chemical structures. Related important pyrazole fused scaffolds like indazole, pyrrolo[1,2-b]pyrazole, pyrazolo[4,3-b]pyridine, pyrazolo[1,5-a]pyrimidine, or pyrazolo[3,4-d]pyrimidine are beyond the subject of this work. |
| first_indexed | 2024-03-11T00:47:58Z |
| format | Article |
| id | doaj.art-780606446a7b464196f22eb220eda6ff |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-11T00:47:58Z |
| publishDate | 2023-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-780606446a7b464196f22eb220eda6ff2023-11-18T20:40:58ZengMDPI AGMolecules1420-30492023-07-012814535910.3390/molecules28145359The Importance of the Pyrazole Scaffold in the Design of Protein Kinases Inhibitors as Targeted Anticancer TherapiesGeorge Mihai Nitulescu0Gheorghe Stancov1Oana Cristina Seremet2Georgiana Nitulescu3Dragos Paul Mihai4Cosmina Gabriela Duta-Bratu5Stefania Felicia Barbuceanu6Octavian Tudorel Olaru7Faculty of Pharmacy, Carol Davila University of Medicine and Pharmacy, Traian Vuia 6, 020956 Bucharest, RomaniaFaculty of Pharmacy, Carol Davila University of Medicine and Pharmacy, Traian Vuia 6, 020956 Bucharest, RomaniaFaculty of Pharmacy, Carol Davila University of Medicine and Pharmacy, Traian Vuia 6, 020956 Bucharest, RomaniaFaculty of Pharmacy, Carol Davila University of Medicine and Pharmacy, Traian Vuia 6, 020956 Bucharest, RomaniaFaculty of Pharmacy, Carol Davila University of Medicine and Pharmacy, Traian Vuia 6, 020956 Bucharest, RomaniaFaculty of Pharmacy, Carol Davila University of Medicine and Pharmacy, Traian Vuia 6, 020956 Bucharest, RomaniaFaculty of Pharmacy, Carol Davila University of Medicine and Pharmacy, Traian Vuia 6, 020956 Bucharest, RomaniaFaculty of Pharmacy, Carol Davila University of Medicine and Pharmacy, Traian Vuia 6, 020956 Bucharest, RomaniaThe altered activation or overexpression of protein kinases (PKs) is a major subject of research in oncology and their inhibition using small molecules, protein kinases inhibitors (PKI) is the best available option for the cure of cancer. The pyrazole ring is extensively employed in the field of medicinal chemistry and drug development strategies, playing a vital role as a fundamental framework in the structure of various PKIs. This scaffold holds major importance and is considered a privileged structure based on its synthetic accessibility, drug-like properties, and its versatile bioisosteric replacement function. It has proven to play a key role in many PKI, such as the inhibitors of Akt, Aurora kinases, MAPK, B-raf, JAK, Bcr-Abl, c-Met, PDGFR, FGFRT, and RET. Of the 74 small molecule PKI approved by the US FDA, 8 contain a pyrazole ring: Avapritinib, Asciminib, Crizotinib, Encorafenib, Erdafitinib, Pralsetinib, Pirtobrutinib, and Ruxolitinib. The focus of this review is on the importance of the unfused pyrazole ring within the clinically tested PKI and on the additional required elements of their chemical structures. Related important pyrazole fused scaffolds like indazole, pyrrolo[1,2-b]pyrazole, pyrazolo[4,3-b]pyridine, pyrazolo[1,5-a]pyrimidine, or pyrazolo[3,4-d]pyrimidine are beyond the subject of this work.https://www.mdpi.com/1420-3049/28/14/5359adenine-mimeticATP-competitiveasciminibavapritinibcrizotinibencorafenib |
| spellingShingle | George Mihai Nitulescu Gheorghe Stancov Oana Cristina Seremet Georgiana Nitulescu Dragos Paul Mihai Cosmina Gabriela Duta-Bratu Stefania Felicia Barbuceanu Octavian Tudorel Olaru The Importance of the Pyrazole Scaffold in the Design of Protein Kinases Inhibitors as Targeted Anticancer Therapies Molecules adenine-mimetic ATP-competitive asciminib avapritinib crizotinib encorafenib |
| title | The Importance of the Pyrazole Scaffold in the Design of Protein Kinases Inhibitors as Targeted Anticancer Therapies |
| title_full | The Importance of the Pyrazole Scaffold in the Design of Protein Kinases Inhibitors as Targeted Anticancer Therapies |
| title_fullStr | The Importance of the Pyrazole Scaffold in the Design of Protein Kinases Inhibitors as Targeted Anticancer Therapies |
| title_full_unstemmed | The Importance of the Pyrazole Scaffold in the Design of Protein Kinases Inhibitors as Targeted Anticancer Therapies |
| title_short | The Importance of the Pyrazole Scaffold in the Design of Protein Kinases Inhibitors as Targeted Anticancer Therapies |
| title_sort | importance of the pyrazole scaffold in the design of protein kinases inhibitors as targeted anticancer therapies |
| topic | adenine-mimetic ATP-competitive asciminib avapritinib crizotinib encorafenib |
| url | https://www.mdpi.com/1420-3049/28/14/5359 |
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