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

ABSTRACT: Several anti-human epidermal growth factor receptor 2 (HER2) treatments have improved the landscape of HER2-positive breast cancer (BC) over the past few years; due to the heterogeneity of the disease itself, the drug resistance mechanisms and relapse are still the main issue in HER2-positive BC. Here, we intended to target simultaneous inhibition of both poly ADP-ribose polymerase 1 (PARP1) and cyclin-dependent kinase 12 (CDK12) that have had an impact on this disease up to their implementation in clinical practice. We successfully screened PARP1 inhibitors (PARPis) containing bicyclic tetrahydropyridine pyrimidines with antitumor activity. Most synthesized compounds with various alcohols were more effective at killing tumor cells than olaparib (ola), especially in HER2-positive cancer ce

SUBMITTER: Lin S 

PROVIDER: S-EPMC10357520 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature