PF-562271

Focal Adhesion Kinase (FAK) is an important target for tumor therapy and is closely related to tumor cell genesis and progression. In this paper, we selected 46 FAK inhibitors with anticancer activity in the pyrrolo pyrimidine backbone to establish 3D/2D-QSAR models to explore the relationship between inhibitory activity and molecular structure. We have established two ideal models, namely, the Topomer CoMFA model (__-mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"-__q2= 0.715, __-mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"-__r2= 0.984) and the Holographic Quantitative Structure-Activity Relationship (HQSAR) model (__-mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"-__q2= 0.707, __-mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"-__r2= 0.899). Both models demonstrate excellent external prediction capabilities.Based on the QSAR results, we designed 20 structurally modified novel compounds, which were subjected to molecular docking and molecular dynamics studies, and the results showed that the new compounds formed many robust interactions with residues within the active pocket and could maintain stable binding to the receptor proteins. This study not only provides a powerful screening tool for designing novel FAK inhibitors, but also presents a series of novel FAK inhibitors with high micromolar activity that can be used for further characterization. It provides a reference for addressing the shortcomings of drug metabolism and drug resistance of traditional FAK inhibitors, as well as the development of novel clinically applicable FAK inhibitors.

Cellular senescence is an irreversible cell cycle arrest caused by various stressors that damage cells. Over time, senescent cells accumulate and contribute to the progression of multiple age‐related degenerative diseases. It is believed that these cells accumulate partly due to their ability to evade programmed cell death through the development and activation of survival and antiapoptotic resistance mechanisms; however, many aspects of how these survival mechanisms develop and activate are still unknown. By analyzing transcriptomic signature profiles generated by the LINCS L1000 project and using network‐based methods, we identified various genes that could represent new senescence‐related survival mechanisms. Additionally, employing the same methodology, we identified over 600 molecules with potential senolytic activity. Experimental validation of our computational findings confirmed the senolytic activity of Fluorouracil, whose activity would be mediated by a multitarget mechanism, revealing that its targets AURKA, EGFR, IRS1, SMAD4, and KRAS are new senescent cell antiapoptotic pathways (SCAPs). The development of these pathways could depend on the stimulus that induces cellular senescence. The SCAP development and activation mechanisms proposed in this work offer new insights into how senescent cells survive. Identifying new antiapoptotic resistance targets and drugs with potential senolytic activity paves the way for developing new pharmacological therapies to eliminate senescent cells selectively.