zstk474 and Neoplasms

Phosphatidylinositol-3 kinase (PI3K) pathway is one of the most frequently activated pathogenic signaling cascades in human malignancies. PI3K is genetically mutated or overexpressed in a wide variety of cancers including ovarian, breast, prostate, gastric, colorectal, glioblastoma, endometrial and brain cancers. Studies are still ongoing to find more efficient and selective PI3K inhibitors or dual PI3K inhibitors to overcome the resistance to the current inhibitors. This review will focus on the three main classes of PI3K inhibitors with efficacious antitumor activity which are: isoform-selective PI3K inhibitors, dual pan-Class I PI3K/m-TOR inhibitors, and pan-Class I PI3K inhibitors without significant m-TOR activity. Isoform-selective PI3K inhibitors are classified into four classes IA, IB, II, and III. Moreover, SAR among each class, together with the biological activity will be discussed. In addition, the new scopes for the design of novel candidates to overcome emerging resistance will be highlighted as well.

Topics: Antineoplastic Agents; Drug Design; Drug Resistance, Multiple; Humans; Molecular Targeted Therapy; Mutation; Neoplasms; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Protein Kinase Inhibitors

This review covering literature reports from the beginning of this century to 2016 describes the synthetic pathways, the antitumor activity, the structure-activity relationship and, whenever reported, the possible mechanism of action of 1,3,5-triazine derivatives as well as of their hetero-fused compounds. Many 1,3,5-triazine derivatives, both uncondensed and hetero-fused, have shown remarkable antitumor activities and some of them reached clinical development.

Topics: Animals; Antineoplastic Agents; Chemistry Techniques, Synthetic; Drug Discovery; Humans; Models, Molecular; Neoplasms; Structure-Activity Relationship; Triazines

Over the past few decades, panels of human cancer cell lines have made a significant contribution to the discovery and development of anticancer drugs. The National Cancer Institute 60 (NCI60), which consists of 60 cell lines from various human cancer types, remains the most powerful human cancer cell line panel for high throughput screening of anticancer drugs. The development of JFCR39, comprising a panel of 39 human cancer cell lines coupled with a drug-activity database, was based on NCI60. Like NCI60, JFCR39 not only provides disease-oriented information but can also predict the action mechanism or molecular target of a given antitumor agent by utilizing the COMPARE algorithm. The molecular targets of ZSTK474 as well as several other antitumor agents have been identified by using JFCR39 and some of these compounds have since entered clinical trials. In this review, we will describe human cancer cell line panels particularly JFCR39 and its application in the discovery and/or development of anticancer drug candidates.

Topics: Algorithms; Animals; Antineoplastic Agents; Cell Line, Tumor; Drug Discovery; Drug Screening Assays, Antitumor; Humans; National Cancer Institute (U.S.); Neoplasms; Triazines; United States

Phosphatidylinositol 3-kinase α (PI3Kα) is one of the most attractive therapeutic targets for cancer treatment. As our continuing endeavor to discover isoform and/or mutant selective class of PI3K inhibitors, herein we report the optimization of a structurally novel PI3Kα H1047R mutant inhibitor Hit-02 (EC

Topics: Antineoplastic Agents; Apoptosis; Cell Proliferation; Drug Screening Assays, Antitumor; HCT116 Cells; Humans; Neoplasms; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Point Mutation; Protein Kinase Inhibitors; Structure-Activity Relationship