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As one of the key phosphatidylinositol 3-kinase-related kinases (PIKKs) family members, ataxia telangiectasia and RAD3-related protein kinase (ATR) is crucial in maintaining mammalian cell genomic integrity in DNA damage response (DDR) and repair pathways. Dysregulation of ATR has been found across different cancer types. In recent years, the inhibition of ATR has been proven to be effective in cancer therapy in preclinical and clinical studies. Importantly, tumor-specific alterations such as ATM loss and Cyclin E1 (CCNE1) amplification are more sensitive to ATR inhibition and are being exploited in synthetic lethality (SL) strategy. Besides SL, synergistic anticancer effects involving ATRi have been reported in an increasing number in recent years. This review focuses on the recent advances in different forms of synergistic antitumor effects, summarizes the pharmacological benefits and ongoing clinical trials behind the biological mechanism, and provides perspectives for future challenges and opportunities. The hope is to draw awareness to the community that targeting ATR should have great potential in developing effective anticancer medicines.

Histone deacetylases (HDACs) are validated targets for the development of anticancer drugs in epigenetics. We have designed and synthesized a series of novel HDAC inhibitors based on pyrrolo[2,3‐d]pyrimidine and pyrrolo[2,3‐b]pyridine scaffolds. Compound B3 {(E)‐3‐(4‐(((1‐(7H‐pyrrolo[2,3‐d]pyrimidin‐4‐yl)piperidin‐4‐yl)amino)methyl)phenyl)‐N‐hydroxyacrylamide} exhibits potent inhibitory activity against HDACs 1, 2, 3, 6, and 8 with IC50 values of 5.2, 6.0, 8.8, 4.4, and 173.0 nM, respectively. It exhibited potent antiproliferative effects against three tumour cell lines (IC50 values of 0.13, 0.37, and 1.11 μM, against MV‐4‐11, K562, and WSU‐DLCL‐2 cells, respectively) with two‐ to sixfold improvement relative to suberoylanilide hydroxamic acid (SAHA). Mechanistic studies on WSU‐DLCL‐2 cells revealed that B3 exhibits anticancer effects through the induction of G0/G1‐phase arrest and promotion of apoptosis. The results of this study warrant further investigation of this compound series for the treatment of hematological malignancy.