Type I protein arginine methyltransferases (PRMTs) play significant roles in various diseases, including cancer. The inhibition of type I PRMTs significantly suppresses the growth of breast cancer, particularly triple-negative breast cancer (TNBC). The development of potent and selective type I PRMTs inhibitors has become a research hotspot in recent years. In this study, a series of six-membered fused five-membered heterocyclic derivatives were designed via a scaffold hopping strategy. Through structural optimization, the pyrazole derivative B9, namely SKLB06329, was obtained. This compound exhibited inhibitory activity against Type I PRMTs at the nanomolar to low nanomolar level and showed good selectivity for PRMT5/7 and various lysine methyltransferases. SKLB06329 could significantly inhibit the proliferation of TNBC cells, induce apoptosis, and suppress the expression of asymmetric dimethylarginine (ADMA) within cells. When administered intravenously, it demonstrated favorable pharmacokinetic properties. SKLB06329 can serve as an effective lead compound for further research, providing a new strategy for the treatment of TNBC.Copyright © 2025 Elsevier Masson SAS. All rights reserved.