2-amino-8-ethyl-4-methyl-6-(1H-pyrazol-5-yl)-7-pyrido[2-3-d]pyrimidinone and Neoplasms

Aberrant activation of the phosphoinositide 3-kinase (PI3K) signaling network is a key event in many human cancers and therefore enormous efforts have been made in the development of PI3K inhibitors. However, due to intrinsic and acquired resistance as well as poor drug tolerance, limited therapeutic efficacy has been achieved with these agents. In view of the fact that PI3K inhibitors can show synergistic antitumor effects with other cancer agents, namely mammalian target of rapamycin (mTOR) inhibitors, histone deacetylase (HDAC) inhibitors and mitogen-activated protein kinase (MEK) inhibitors, dual inhibition of both targets by a single-molecule is regarded as a promising complementary or alternative therapeutic strategy to overcome the drawbacks of just PI3K monotherapy. In this review, we discuss the theoretical foundation for designing PI3K-based dual-target inhibitors and summarize the structure-activity relationships and clinical progress of these dual-binding agents.

Topics: Animals; Antineoplastic Agents; Cell Proliferation; Drug Design; Humans; Molecular Structure; Neoplasms; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors

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