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Considerable progress has been made in the development of anticancer agents over the past few decades, and a lot of new anticancer agents from natural and synthetic sources have been produced. Among heterocyclic compounds, pyrimidine-fused bicyclic heterocycles possess a variety of biological activities such as anticancer, antiviral, etc. To date, 147 pyrimidine-fused bicyclic heterocycles have been approved for clinical assessment or are currently being used in clinic, 57 of which have been approved by FDA for clinical treatment of various diseases, and 22 of them are being used in the clinic for the treatment of different cancers. As the potentially privileged scaffolds, pyrimidine-fused bicyclic heterocycles may be used to discover new drugs with similar biological targets and improved therapeutic efficacy. This review aims to provide an overview of the anticancer applications and synthetic routes of 22 approved pyrimidine-fused bicyclic heterocyclic drugs in clinic. Image 1 • 22 pyrimidine-fused bicyclic heterocyclic drugs have been approved for the treatment of cancers. • Pyrimidine-fused bicyclic heterocycles could be used as privileged structures for further development of new drugs. • The synthetic routes of 22 drugs and their anticancer applications are summarized. [ABSTRACT FROM AUTHOR]

Abstract The histone lysine specific demethylase 1 (LSD1/KDM1A) is implicated in the development of cancers, targeting LSD1 has been recognized as a promising strategy for cancer therapy. To date, some small-molecule inhibitors are currently being investigated in clinical trials. Herein we report the design, synthesis and biochemical characterization of [1,2,4]triazolo[1,5- a ]pyrimidine derivatives as new LSD1 inhibitors. Of these compounds, compound C26 inhibited LSD1 in a reversible manner (IC 50 = 1.72 μM) and showed selectivity to LSD1 over MAO-A/B. Besides, compound C26 displayed FAD-competitive binding to LSD1. Interestingly, C26 did not inhibit horseradish peroxidase (HRP) and quench H 2 O 2 , thus excluding the possibility that LSD1 inhibition by C26 was due to the HRP inhibition and consumption of H 2 O 2. In LSD1 overexpressed A549 cells, compound C26 concentration-dependently induced accumulation of H3K4me1/me2 and H3K9me2 and showed cellular target engagement to LSD1. Additionally, compound C26 significantly inhibited migration of A549 cells in a concentration-dependent manner, further western blot analysis showed that C26 increased expression levels of epithelial cell markers E-Cadherin and Claudin-1, down-regulated mesenchymal cell marker N-Cadherin and the upstream transcription factors Snail and Slug. Docking studies were also performed to rationalize the potency of C26 toward LSD1. To conclude, the [1,2,4]triazolo[1,5- a ]pyrimidine could serve as a promising scaffold for the development of new LSD1 inhibitors. Graphical abstract Image 1 Highlights • A new series of [1,2,4]triazolo[1,5- a ]pyrimidine derivatives were designed as new LSD1 inhibitors. • C26 inhibited LSD1 reversibly and showed selectivity to LSD1 over MAO-A/B. • C26 concentration-dependently induced accumulation of H3K4/9 substrates and showed cellular target engagement to LSD1 in A549 cells. • C26 significantly inhibited migration of A549 cells in a concentration-dependent manner. • The [1,2,4]triazolo[1,5- a ]pyrimidine could serve as a promising scaffold for the development of new LSD1 inhibitors. [ABSTRACT FROM AUTHOR]

In this work, a novel series of tofacitinib analogs were designed and synthesized based on the scaffold hybridization strategy and then evaluated for their antiproliferative activity toward three gastric cancer cell lines, leading to the identification of compound C18 which exhibited potent inhibitory activity against MGC-803 cell lines with an IC 50 value of 2.68 μM. Compound C18 could effectively inhibit the colony formation, suppress the cell migration and induce apoptosis of MGC-803 cells through activating the p38 and JNK signaling pathways, while C18 showed no obvious effect on the cell cycle distribution in MGC-803 cells. In addition, C18 could initiate mitochondrial dysfunction of MGC-803 cells. Besides, in vivo antitumor studies indicated that C18 could inhibit gastric cancer tumor growth in vivo without obvious global toxicity. Image 1 • New tofacitinib analogs were designed based on the scaffold hybridization strategy. • C18 effectively inhibits colony formation and cell migration of MGC-803 cells. • C18 induces apoptosis of MGC-803 cells through activation of the p38 and JNK signaling pathways. • C18 induces mitochondrial dysfunction of MGC-803 cells. • C18 effectively inhibits tumor growth of xenograft model bearing MGC-803 cells. [ABSTRACT FROM AUTHOR]