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

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.

Inhibiting the Extracellular Signal-regulated Kinase 1/2 (ERK1/2) Cascade in Cancer and the Heart: for Better or Worse, in Sickness and Health?

“…* ATP competitive; ** RAF dimer inhibitor; *** allosteric inhibitor; § other inhibitor type. ** [122] * [123] ** [122] ** [124] * [125] § [41,126] * [127] * [128] *** [129] *** [130] * [131] ? [132] ?…”

Recent Advances in the Development of Pyrazole Derivatives as Anticancer Agents

“…The latest review has summarized 42 protein kinase inhibitors containing an unfused pyrazole ring that are in clinical testing stages, including inhibitors of AKT, EGFR/VEGFR, MAPK, BRAF, JAK, C-Met, BTK, etc. Representative drug candidates include afuesertib, lazertinib, dexmetinib, encorafenib, ruxolitinib, crizotinib, and pirobrutinib [ 44 ].…”

“…Compared to pyrazole-based inhibitors targeting common tumor-associated targets like EGFR and VEGFR, the development of pyrazole-based BRAF inhibitors has been relatively limited thus far, likely due to challenges such as resistance [ 66 ]. Encorafenib is one of the few reported pyrazole-cored agents used to target BRAF [ 44 ]. Beyond encorafenib, scientists continue to synthesize and optimize other pyrazole derivatives targeting BRAF, with the goal of achieving enhanced selectivity and antitumor efficacy.…”

“…The recent review has reported three unfused pyrazole-containing multi-kinase inhibitors currently in clinical trials: crizotinib, merestinib, and ilorasertib [ 44 ]. Additionally, extensive efforts have been made to develop novel multitargeted kinase inhibitors incorporating pyrazole core scaffold for precision oncology.…”

Structure–Activity Relationship Studies on Highly Functionalized Pyrazole Hydrazones and Amides as Antiproliferative and Antioxidant Agents

“…Pyrazole scaffold is a pharmaceutically relevant moiety [1][2][3][4][5][6], and pyrazole-containing compounds show antiviral [7], antibacterial [8,9], antimalarial [10], anti-inflammatory [11], antidiabetic [12], antiglaucoma [13,14], and anticancer [15][16][17][18][19][20][21] properties. Furthermore, pyrazole scaffolds are shared by several protein kinase inhibitors, including FDA-approved drugs Avapritinib, Asciminib, Crizotinib, Encorafenib, Erdafitinib, Pralsetinib, Pirtobrutinib, and Ruxolitinib (Figure 1) [22,23]. Among pyrazole series, aminopyrazoles (APs) represent an attractive framework in medicinal chemistry [24][25][26]; indeed, the decoration of the pyrazole ring with amino substituents at different positions led to the isolation of pharmacologically active derivatives including analgesic (e.g., Aminophenazone and Metamizole; Figure 1) and antitumor (e.g., AT7519, AT9283, Prexasertib, Pirtobrutinib/Jaypirca™; Figure 1) agents [23,[27][28][29][30][31][32][33].…”