Synthesis of Novel Dual Target Inhibitors of CDK12 and PARP1 and Their Antitumor Activities in HER2-Positive Breast Cancers

Several anti-human epidermal growth factor receptor 2(HER2) treatmentshave improved the landscape of HER2-positive breast cancer (BC) overthe past few years; due to the heterogeneity of the disease itself,the drug resistance mechanisms and relapse are still the main issuein HER2-positive BC. Here, we intended to target simultaneous inhibitionof both poly ADP-ribose polymerase 1 (PARP1) and cyclin-dependentkinase 12 (CDK12) that have had an impact on this disease up to theirimplementation in clinical practice. We successfully screened PARP1inhibitors (PARPis) containing bicyclic tetrahydropyridine pyrimidineswith antitumor activity. Most synthesized compounds with various alcoholswere more effective at killing tumor cells than olaparib (ola), especiallyin HER2-positive cancer cells. Among them, compound 9 showed potent inhibitory effects on PARP1 enzymatic activity andthe PAR protein level; moreover, the expression of CDK12 was inhibitedby compound 9. Overall, compound 9 exhibiteda significant antitumor effect by inhibiting DNA damage repair intumors.