Pictilisib

Novel anti-breast cancer benzoxazoles were synthesized applying the scaffold hopping and molecular hybridization approaches. MTT assay showed that 6 and 9b were 4.5 and 2 times more potent than doxorubicin against MCF-7 cells, while 9a and 13b were 10 and 7.5 times more effective against MDA-MB-231 cells, respectively. The four compounds showed good safety profiles toward MCF-10A cells' growth. Enzyme inhibition assays identified 9b as a potent aromatase (ARO) inhibitor, exhibiting twice the potency of letrozole. 13d was more potent PI3Kα inhibitor than pictilisib, while 6, 9a, and 13b were multi-kinase inhibitors. Compound 9a was 2 and 2.5 times more potent than lapatinib against EGFR^WT and EGFR^L858R, besides being a selective PI3Kα/β inhibitor, surpassing pictilisib by 3 and 1.5 times, respectively. Compound 13b exhibited comparable EGFR^L858R inhibition to lapatinib and outperformed pictilisib against PI3Kα, PI3Kβ, and PI3Kδ. Compound 6 showed greater ARO inhibition than letrozole, while being slightly less potent than pictilisib against PI3Kα and PI3Kβ. The four compounds downregulated p-ERK and/or p-AKT levels more effectively than letrozole or lapatinib. They elevated Beclin-1 levels and increased caspase-9 levels with 6, 9a and 9b inducing higher %total apoptosis than doxorubicin in annexin V/ propidium iodide assay. Moreover, 9a reduced cell migration and invasion percentages to 9.22 and 16.95 %, respectively, in MDA-MB-231-treated cells, thereby suppressed metastasis. Docking studies supported the in vitro enzymatic inhibition assays results. Thus, 9b and 13d are potent anti-breast cancer benzoxazoles with selective ARO and PI3kα inhibition activity, respectively, while 6, 9a, and 13b are multi-target inhibitors exhibiting other anticancer synergistic mechanisms.

Objective. Spontaneous network bursts (NBs) are critical for neuronal circuit development, influencing synaptogenesis and functional organization. While JNK and PI3K-Akt signaling pathways are known to regulate synaptic plasticity, their specific roles in governing NBs dynamics and functional network organization remain poorly understood. This study investigates the roles of JNK and PI3K-Akt signaling in regulating spontaneous NBs dynamics and network organization in cultured neuronal networks. Approach. Using longitudinal microelectrode array (MEA) recordings from cultured cortical neurons (DIV14-49), we pharmacologically inhibited JNK (SP600125, JNK-IN-8) and PI3K-Akt (LY294002, GDC-0941) pathways. We quantitatively analyzed NBs profiles (maximum firing rate/MFR, burst length/BL, rising phase/RP) and functional network properties (modularity, betweenness centrality) during development. Main results. JNK inhibition increased MFR but reduced RP and FP, and decreased betweenness centrality and network modularity, particularly in DIV21. PI3K-Akt inhibition caused delayed effects: decreased MFR at DIV49 with increased RP, while enhancing network modularity. Developmental analysis revealed a transition from core-node-driven NBs (strong MFR-betweenness and BL-betweenness correlation at DIV14) to modularly organized NBs (strong BL-modularity and MFR-modularity correlation at DIV49), with pathway inhibitors differentially altering these relationships. Significance. Our findings demonstrate that JNK and PI3K-Akt pathways play distinct temporal roles in regulating NBs dynamics and network organization. JNK signaling is crucial for maintaining early core-node functionality, whereas PI3K-Akt signaling promotes the development of mature modular architecture. Our findings enhance the understanding of how molecular signaling influences neuronal network dynamics, contributing to a broader framework for studying neurodevelopmental principles.