Polypharmacology is a promising paradigm in modern drug discovery. Herein, we have discovered a series of novel PI3K and HDAC dual inhibitors in which the hydroxamic acid moiety as the zinc binding functional group was introduced to a quinazoline-based PI3K pharmacophore through an appropriate linker. Systematic structure–activity relationship studies resulted in lead compounds 23 and 36 that simultaneously inhibited PI3K and HDAC with nanomolar potencies and demonstrated favorable antiproliferative activities. Compounds 23 and 36 efficiently modulated the expression of p-AKT and Ac-H3, arrested the cell cycle, and induced apoptosis in HCT116 cancer cells. Following pharmacokinetic studies, 23 was further evaluated in HCT116 and HGC-27 xenograft models to show significant in vivo anticancer efficacies with tumor growth inhibitions of 45.8% (po, 150 mg/kg) and 62.6% (ip, 30 mg/kg), respectively. Overall, this work shows promise in discovering new anticancer therapeutics by the approach of simultaneously targeting PI3K and HDAC pathways with a single molecule.

Increased phosphatidylinositol 3-kinase (PI3K) signaling is among the most common alterations in cancer, spurring intensive efforts to develop new cancer therapeutics that target this pathway. In this work, we discovered a series of novel 2-amino-4-methylquinazoline derivatives through a hybridization and subsequent scaffold hopping approach that were highly potent class I PI3K inhibitors. Lead optimization resulted in several promising compounds (e.g., 19, 20, 37, and 43) with nanomolar PI3K potencies, prominent antiproliferative activities, favorable PK profiles, and robust in vivo antitumor efficacies. More interestingly, compared with 19 and 20, 37 and 43 demonstrated improved brain penetration and in vivo efficacy in an orthotopic glioblastoma xenograft model. Furthermore, preliminary safety assessments including hERG channel inhibition, AMES, CYP450 inhibition, and single-dose toxicity were performed to characterize their toxicological properties.

Aberrant activation of the PI3K pathway has been intensively targeted for cancer therapeutics for decades, leading to more than 40 PI3K inhibitors advanced into clinical trials. However, it is increasingly noticed that PI3K inhibitors often showed limited efficacy as well as a number of serious on-target adverse effects during the clinical development. In this work, we designed and synthesized a novel photocaged PI3K inhibitor 1, which could be readily activated by UV irradiation to release a highly potent PI3K inhibitor 2. Upon UV irradiation, the photocaged inhibitor 1 demonstrated remarkably enhanced antiproliferative activity against multiple cancer cell lines and significant efficacy in the patient-derived tumor organoid model. Furthermore, 1 also showed favorable anticancer activity in an in vivo zebrafish xenograft model. Taken together, the photocaged PI3K inhibitor 1 represents a promising avenue for novel therapeutics toward precise cancer treatment.

Gastrointestinal cancer is a prevalent disease with high morbidity and mortality. Tissue factor pathway inhibitor 2 (TFPI2) gene could protect the extracellular matrix of cancer cells from degradation and tumor invasion. The goal of our study was to estimate the diagnostic value of TFPI2 hypermethylation in gastric cancer (GC) and colorectal cancer (CRC). TFPI2 methylation was measured by quantitative methylation-specific polymerase chain reaction (qMSP) method in 114 GC and 80 CRC tissues and their paired non-tumor tissues. Our results showed that TFPI2 methylation was significantly higher in tumor tissues (GC: 29.940% vs. 12.785%, P < 0.001; CRC: 26.930% vs. 5.420%, P < 0.001). The methylation level of TFPI2 in colorectal tumor tissues was significantly higher than that in colorectal normal tissues (26.930% versus 0.002%, P < 0.00001). In GC, TFPI2 hypermethylation yielded an area under the curve (AUC) of 0.762 (95% CI: 0.696–0.828) with a sensitivity of 68% and a specificity of 83%. In CRC, TFPI2 hypermethylation yielded an AUC of 0.759 (95% CI: 0.685–0.834) with a sensitivity of 61% and a specificity of 84%. Similarly, TCGA data also supported TFPI2 hypermethylation was a promising diagnostic marker for GC and CRC. Moreover, the dual-luciferase reporter assay showed TFPI2 fragment could upregulate gene expression (fold change = 5, P = 0.005). Data mining further indicated that TFPI2 expression in CRC cell lines was significantly increased after 5’-AZA-deoxycytidine treatment (fold change > 1.37). In conclusion, TFPI2 hypermethylation might be a promising diagnostic biomarker for GC and CRC.