Due to the advantages in efficacy and safety compared with traditional chemotherapy drugs, targeted therapeutic drugs have become mainstream cancer treatments. Since the first tyrosine kinase inhibitor imatinib was approved to enter the market by the US Food and Drug Administration (FDA) in 2001, an increasing number of small-molecule targeted drugs have been developed for the treatment of malignancies. By December 2020, 89 small-molecule targeted antitumor drugs have been approved by the US FDA and the National Medical Products Administration (NMPA) of China. Despite great progress, small-molecule targeted anti-cancer drugs still face many challenges, such as a low response rate and drug resistance. To better promote the development of targeted anti-cancer drugs, we conducted a comprehensive review of small-molecule targeted anti-cancer drugs according to the target classification. We present all the approved drugs as well as important drug candidates in clinical trials for each target, discuss the current challenges, and provide insights and perspectives for the research and development of anti-cancer drugs.

Metformin is a widely used antidiabetic drug that exerts cardiovascular protective effects in patients with diabetes. How metformin protects against diabetes-related cardiovascular diseases remains poorly understood. Here, we show that metformin abated the progression of diabetes-accelerated atherosclerosis by inhibiting mitochondrial fission in endothelial cells. Metformin treatments markedly reduced mitochondrial fragmentation, mitigated mitochondrial-derived superoxide release, improved endothelial-dependent vasodilation, inhibited vascular inflammation, and suppressed atherosclerotic lesions in streptozotocin (STZ)-induced diabetic ApoE−/− mice. In high glucose–exposed endothelial cells, metformin treatment and adenoviral overexpression of constitutively active AMPK downregulated mitochondrial superoxide, lowered levels of dynamin-related protein (Drp1) and its translocation into mitochondria, and prevented mitochondrial fragmentation. In contrast, AMPK-α2 deficiency abolished the effects of metformin on Drp1 expression, oxidative stress, and atherosclerosis in diabetic ApoE−/−/AMPK-α2−/− mice, indicating that metformin exerts an antiatherosclerotic action in vivo via the AMPK-mediated blockage of Drp1-mediated mitochondrial fission. Consistently, mitochondrial division inhibitor 1, a potent and selective Drp1 inhibitor, reduced mitochondrial fragmentation, attenuated oxidative stress, ameliorated endothelial dysfunction, inhibited inflammation, and suppressed atherosclerosis in diabetic mice. These findings show that metformin attenuated the development of atherosclerosis by reducing Drp1-mediated mitochondrial fission in an AMPK-dependent manner. Suppression of mitochondrial fission may be a therapeutic approach for treating macrovascular complications in patients with diabetes.

Evidence accumulated over the past several years indicates that the AMP-activated protein kinase (AMPK) 2 may be a therapeutic target for treating insulin resistance and type 2 diabetes (1). AMPK is a heterotrimeric protein formed by an ␣ subunit, which contains the catalytic activity, and by the ␤ and ␥ regulatory subunits important in maintaining stability of the heterotrimer complex (2). AMPK belongs to a family of energy-sensing enzymes functioning as a "fuel gauge" that monitors changes in the energy status of a cell (3, 4). When activated, AMPK shuts down anabolic pathways and promotes catabolism in response to an elevated AMP/ATP ratio by down-regulating the activity of several key enzymes of intermediary metabolism (4). Two primary acute consequences of AMPK activation are 1) an increase in glucose uptake by induction of glucose 4 transporter microvesicle cytoplasm to membrane translocation and fusion and 2) an increase in fatty acid oxidation by phosphorylation and inactivation of acetyl-CoA carboxylase (ACC), the rate-limiting enzyme in fatty acid synthesis (5). Therefore, the AMPK signal pathways are thought to play a central role in the regulation of cellular glucose and lipid homeostasis. The control of AMPK activity is complex, and the classic view is that AMPK is activated allosterically by an increase in the intracellular AMP/ATP ratios and/or by the phosphorylation of threonine 172 within the ␣ subunit. Several protein kinases responsible for this phosphorylation have been identified. They include Peutz-Jeghers syndrome kinase LKB1 (LKB1) (6), and the Ca 2ϩ /calmodulin-dependent protein kinase kinase (7). Protein phosphorylation signal transduction systems are balanced and regulated delicately by both phosphatase and kinase. Since AMPK is activated by (a) protein kinase(s) at the threonine 172 residue, one can easily assume that AMPK can be regulated negatively by (a) serine/threonine phosphatase(s). To date, a wide range of physiological stressors, pharmacological agents, and hormones associated with increase in the intracellular AMP/ATP ratios have been demonstrated to activate AMPK (8). AMPK is also thought to be regulated by glycogen (9), which is the major cellular storage form of carbohydrates and thus, an additional indicator of cellular energy status. Lipids are the other major energy source for cellular metabolism. Recent studies (10, 11) in heart and liver have revealed that AMPK may be sensitive to the "lipid status" of a cell, and activation may be influenced by intracellular fatty BSA, bovine serum albumin; eNOS, endothelial nitric-oxide synthase; LKB1, Peutz-Jeghers syndrome kinase LKB1; OA, okadaic acid; ONOO Ϫ , peroxynitrite; VSMC, vascular smooth muscle cell; siRNA, short interference RNA; FFA, free fatty acid; EBM, endothelial basal medium; 2-BrP, 2-bromopalmitate; HFD, high fat diet; PP2C, protein phosphatase 2C.

N 6 -methyladenosine (m 6 A) is the most widespread internal mRNA modification in humans. Despite recent progress in understanding the biological roles of m 6 A, the inability to install m 6 A site-specifically in individual transcripts has hampered efforts to elucidate causal relationships between the presence of a specific m 6 A and phenotypic outcomes. Here we demonstrate that nucleus-localized dCas13 fusions with a truncated METTL3 methyltransferase domain and cytoplasm-localized fusions with a modified METTL3:METTL14 methyltransferase complex can direct site-specific m 6 A incorporation in distinct cellular compartments, with the former fusion protein having particularly low off-target activity. Independent cellular assays across multiple sites confirm that this targeted RNA methylation (TRM) system mediates efficient m 6 A installation in endogenous RNA transcripts with high specificity. Finally, we show that TRM can induce m 6 A-mediated changes to transcript abundance and alternative splicing. These findings establish TRM as a tool for targeted epitranscriptome engineering to help reveal the effect of individual m 6 A modifications and dissect their functional roles.