Attia Mohamed H, Lasheen Deena S, Samir Nermin, Taher Azza T, Abdel-Aziz Hatem A, Abou El Ella Dalal A
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, October 6 University (O6U), Giza 12585, Egypt.
Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ain Shams University, Cairo 11566, Egypt.
Pharmaceuticals (Basel). 2024 Dec 10;17(12):1667. doi: 10.3390/ph17121667.
The increasing prevalence of drug resistance in cancer therapy underscores the urgent need for novel therapeutic approaches. Dual enzyme inhibitors, targeting critical kinases such as CDK2 and TRKA, represent a promising strategy. The goal of this investigation was to design, synthesize, and evaluate a set of pyrazolo[1,5-]pyrimidine derivatives for their dual inhibition potential toward CDK2 and TRKA kinases, along with their potential antiproliferative against cancer cell lines.
A set of pyrazolo[1,5-]pyrimidine derivatives (-, -, and ) was synthesized and subjected to in vitro enzymatic assays to determine their inhibitory activity against CDK2 and TRKA kinases. Selected compounds were further assessed for antiproliferative effects across the set of 60 cell lines from the NCI, representing various human cancer types. Additionally, simulations of molecular docking were conducted to explore the modes of binding for the whole active compounds and compare them with known inhibitors.
Compounds and exhibited potent dual inhibitory activity, showing an IC = 0.09 µM and 0.23 µM against CDK2, and 0.45 µM against TRKA, respectively. These results were comparable to reference inhibitors ribociclib (CDK2, IC = 0.07 µM) and larotrectinib (TRKA, IC = 0.07 µM). Among the studied derivatives, compound displayed a notable broad-spectrum anticancer activity, achieving a mean growth inhibition (GI%) of 43.9% across 56 cell lines. Molecular docking simulations revealed that the synthesized compounds adopt modes of binding similar to those of the lead inhibitors. Conclusions In this study, prepared pyrazolo[1,5-]pyrimidine derivatives demonstrated significant potential as dual CDK2/TRKA inhibitors, and showed potent anticancer activity toward diverse cancer cell lines. These findings highlight their potential as key compounds for the design of novel anticancer therapeutics.
癌症治疗中耐药性的日益普遍凸显了对新型治疗方法的迫切需求。靶向关键激酶如CDK2和TRKA的双酶抑制剂是一种很有前景的策略。本研究的目的是设计、合成并评估一组吡唑并[1,5 -]嘧啶衍生物对CDK2和TRKA激酶的双重抑制潜力，以及它们对癌细胞系的潜在抗增殖作用。
合成了一组吡唑并[1,5 -]嘧啶衍生物（-、-和 ），并进行体外酶促试验以确定它们对CDK2和TRKA激酶的抑制活性。对选定的化合物进一步评估其对来自美国国立癌症研究所（NCI）的60种细胞系（代表各种人类癌症类型）的抗增殖作用。此外，进行分子对接模拟以探索整个活性化合物的结合模式，并将它们与已知抑制剂进行比较。
化合物 和 表现出强效的双重抑制活性，对CDK2的IC = 0.09 μM和0.23 μM，对TRKA的IC分别为0.45 μM。这些结果与参考抑制剂瑞博西尼（CDK2，IC = 0.07 μM）和拉罗替尼（TRKA，IC = 0.07 μM）相当。在所研究的衍生物中，化合物 表现出显著的广谱抗癌活性，在56种细胞系中平均生长抑制率（GI%）达到43.9%。分子对接模拟表明，合成的化合物采用与先导抑制剂相似的结合模式。结论 在本研究中，制备的吡唑并[1,5 -]嘧啶衍生物显示出作为CDK2/TRKA双重抑制剂的巨大潜力，并对多种癌细胞系表现出强效抗癌活性。这些发现突出了它们作为新型抗癌治疗药物设计关键化合物的潜力。
