PI3Kα inhibitors(Black Diamond Therapeutics)

Cancer remains a major global health challenge, driven in part by dysregulation of key oncogenic signaling pathways such as phosphatidylinositol 3-kinase alpha (PI3Kα), which plays a central role in tumor growth and therapeutic resistance. In this study, an integrative computational strategy combining quantitative structure-activity relationship (QSAR) modeling, drug-likeness and ADMET prediction, and molecular docking was applied to investigate dammarane-type triterpenoid derivatives as potential PI3Kα inhibitors. A dataset of 22 reported compounds was analyzed using multiple linear regression (MLR), partial least squares (PLS), and principal component regression (PCR) models, all of which were rigorously validated by external test sets, Y-randomization, and applicability domain analysis, with the PCR model showing the highest predictive performance (R² = 0.833; R²_test= 0.79). Descriptor analysis identified lipophilicity, electronic distribution, and polar surface properties as key determinants of anticancer activity, while excessive molecular size negatively influenced potency. Guided by these insights, four new derivatives (D1-D4) were rationally designed and evaluated in silico, exhibiting favorable drug-likeness, high predicted oral absorption (89-100%), absence of AMES toxicity, and moderate synthetic accessibility. Molecular docking against PI3Kα (PDB ID: 8TSB) revealed stable binding for all designed compounds, with D1 emerging as the most promising lead, combining strong binding affinity (-5.70 kcal/mol) and favorable interaction patterns within the active site. Overall, this work demonstrates the potential of dammarane-type triterpenoids as PI3Kα-targeted anticancer agents and highlights the value of an integrated, cost-effective computational framework for rational lead identification and optimization, supporting future experimental development in line with global health priorities.

Aberrant activation of PI3K signaling is frequently observed in lung squamous cell carcinoma (LUSC) and is strongly associated with metastasis in advanced-stage patients, but the therapeutic efficacy of PI3K inhibitors and underlying mechanisms in LUSC remain poorly defined. CYH33 is a highly selective PI3Kα inhibitor, which is in phase I/II clinical trials for the therapy of advanced solid tumors including LUSC. In this study, we investigated the efficacy of CYH33 against metastatic LUSC. We showed that CYH33 dose-dependently suppressed the motility of LUSC cells by blocking PI3K signaling and disrupting cytoskeletal structure. Oral administration of CYH33 significantly attenuated the metastasis of orthotopically implanted xenografts derived from LUSC SK-MES-1 cells. RNA-seq and GO enrichment analysis revealed that CYH33 treatment resulted in decreased infiltration of cancer-associated fibroblasts (CAFs) in primary tumors. We demonstrated that CAFs promoted the migration of SK-MES-1 cells by secreting the pro-migratory factors and activating PI3K signaling in tumor cells, which was blocked by CYH33. Moreover, CYH33 concurrently suppressed the trans-differentiation and proliferation of CAFs, thereby reducing the secretion of hepatocyte growth factor (HGF), which likely contributed to its anti-metastatic effect. Consistently, co-inoculation of SK-MES-1 cells with fibroblasts significantly potentiated tumor metastasis in nude mice, whereas CYH33 treatment robustly suppressed this process, accompanied with reduced expression of α-SMA and HGF as well as epithelial-mesenchymal transition (EMT) signature in primary tumor. Furthermore, CYH33 possessed potent activity against the growth of LUSC with hyperactivated PI3K signaling. Collectively, the dual-targeting of CYH33 that directly blocked PI3Kα in tumor cells and disrupted CAF-mediated pro-metastatic signaling supported PI3Kα inhibitors as a potential therapeutic approach for advanced LUSC.