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Review

The Importance of the Pyrazole Scaffold in the Design of Protein Kinases Inhibitors as Targeted Anticancer Therapies

by
George Mihai Nitulescu
,
Gheorghe Stancov
,
Oana Cristina Seremet
,
Georgiana Nitulescu
*,
Dragos Paul Mihai
,
Cosmina Gabriela Duta-Bratu
,
Stefania Felicia Barbuceanu
and
Octavian Tudorel Olaru
Faculty of Pharmacy, Carol Davila University of Medicine and Pharmacy, Traian Vuia 6, 020956 Bucharest, Romania
*
Author to whom correspondence should be addressed.
Molecules 2023, 28(14), 5359; https://doi.org/10.3390/molecules28145359
Submission received: 18 June 2023 / Revised: 8 July 2023 / Accepted: 10 July 2023 / Published: 12 July 2023
(This article belongs to the Special Issue Synthesis and Evaluation of Biologically Active Compounds from Heterocycles Class)
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Abstract

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.
Keywords: adenine-mimetic; ATP-competitive; asciminib; avapritinib; crizotinib; encorafenib; erdafitinib; pralsetinib; pirtobrutinib; ruxolitinib adenine-mimetic; ATP-competitive; asciminib; avapritinib; crizotinib; encorafenib; erdafitinib; pralsetinib; pirtobrutinib; ruxolitinib

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MDPI and ACS Style

Nitulescu, G.M.; Stancov, G.; Seremet, O.C.; Nitulescu, G.; Mihai, D.P.; Duta-Bratu, C.G.; Barbuceanu, S.F.; Olaru, O.T. The Importance of the Pyrazole Scaffold in the Design of Protein Kinases Inhibitors as Targeted Anticancer Therapies. Molecules 2023, 28, 5359. https://doi.org/10.3390/molecules28145359

AMA Style

Nitulescu GM, Stancov G, Seremet OC, Nitulescu G, Mihai DP, Duta-Bratu CG, Barbuceanu SF, Olaru OT. The Importance of the Pyrazole Scaffold in the Design of Protein Kinases Inhibitors as Targeted Anticancer Therapies. Molecules. 2023; 28(14):5359. https://doi.org/10.3390/molecules28145359

Chicago/Turabian Style

Nitulescu, George Mihai, Gheorghe Stancov, Oana Cristina Seremet, Georgiana Nitulescu, Dragos Paul Mihai, Cosmina Gabriela Duta-Bratu, Stefania Felicia Barbuceanu, and Octavian Tudorel Olaru. 2023. "The Importance of the Pyrazole Scaffold in the Design of Protein Kinases Inhibitors as Targeted Anticancer Therapies" Molecules 28, no. 14: 5359. https://doi.org/10.3390/molecules28145359

APA Style

Nitulescu, G. M., Stancov, G., Seremet, O. C., Nitulescu, G., Mihai, D. P., Duta-Bratu, C. G., Barbuceanu, S. F., & Olaru, O. T. (2023). The Importance of the Pyrazole Scaffold in the Design of Protein Kinases Inhibitors as Targeted Anticancer Therapies. Molecules, 28(14), 5359. https://doi.org/10.3390/molecules28145359

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