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

• Published in: Molecules (Basel, Switzerland) Vol. 28; no. 14; p. 5359
• Main Authors: Nitulescu, George Mihai, Stancov, Gheorghe, Seremet, Oana Cristina, Nitulescu, Georgiana, Mihai, Dragos Paul, Duta-Bratu, Cosmina Gabriela, Barbuceanu, Stefania Felicia, Olaru, Octavian Tudorel
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 01.07.2023; MDPI
• Subjects: adenine-mimetic; Adenosine triphosphate; Animals; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; asciminib; ATP-competitive; avapritinib; Binding sites; Cancer; Care and treatment; Crizotinib; Drug approval; Drug Design; Drug development; encorafenib; Enzymes; Humans; Inhibitor drugs; Kinases; Mutation; Nitrogen; Pharmaceutical sciences; Phosphorylation; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - classification; Protein Kinase Inhibitors - pharmacology; Protein kinases; Proteins; Pyrazoles - chemistry; Pyrazoles - pharmacology; Pyrimidines; Review; Signal transduction; Structure-Activity Relationship; adenine-mimetic; ATP-competitive; crizotinib; pralsetinib; ruxolitinib; avapritinib; erdafitinib; pirtobrutinib; asciminib; encorafenib
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules28145359

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.