Advances in Selective c-MET Kinase Inhibitors: Application of Fused [5,6]-Bicyclic Nitrogen-Containing Cores for Anticancer Drug Design,European Journal of Medicinal Chemistry

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Advances in Selective c-MET Kinase Inhibitors: Application of Fused [5,6]-Bicyclic Nitrogen-Containing Cores for Anticancer Drug Design
European Journal of Medicinal Chemistry ( IF 6.0 ) Pub Date : 2024-12-19 , DOI: 10.1016/j.ejmech.2024.117177
Mehdi Valipour, Zahra Zakeri khatir, Adileh Ayati, Asieh Hosseini, Mohammad Sheibani, Hamid Irannejad

Over the past two decades, small molecules bearing [5,6]-bicyclic nitrogen-containing cores have emerged as one of the most extensively studied structures for the development of selective c-MET kinase inhibitors. Structure-activity relationship (SAR) studies have demonstrated that modifying these cores can significantly impact the biological properties of c-MET inhibitors, including safety/toxicity, potency, and metabolic stability. For example, although c-MET kinase inhibitors containing the [1,2,4]triazolo[4,3-b][1,2,4]triazine scaffold (core P) exhibit high inhibitory potency, they often face challenges due to metabolic stability defects. Alternatively, compounds containing [1,2,3]triazolo[4,5-b]pyrazine (core K) and [1,2,4]triazolo[4,3-b]pyridazine (core I) scaffolds demonstrate lower potency but improved metabolic stability, allowing some of them to progress into clinical trials and even be approved as novel anticancer drugs. Fortunately, X-ray crystallography studies have well elucidated key interactions between [5,6]-bicyclic nitrogen-containing cores and crucial amino acid residues within the c-MET active site. These insights emphasize the significance of π-π stacking interactions with Tyr1230 and hydrogen bonding with Asp1222, providing valuable guidance for the targeted design and optimization of selective c-MET kinase inhibitors. Following the identification/introduction of sixteen distinct [5,6]-bicyclic nitrogen-containing cores (cores A-P) utilized in the design of selective c-MET kinase inhibitors over the past two decades, this manuscript offers a comprehensive review of their roles in drug development of anticancer agents, and describes the various synthesis methods employed. The insights presented herein can serve as a resource for better structural optimization of c-MET kinase inhibitors in the future research.

更新日期：2024-12-20

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