Pentagamavunone-1 and its newest derivatives, CCA-1.1, possess an outstanding cytotoxic activity against several cancer cell lines, especially colorectal cancer. We are continuing to explore the anti-colorectal cancer properties of PGV-1 and CCA-1.1 against DMH-induced colorectal cancer rats and expound the potential protein target in colorectal adenocarcinoma. We utilized DMH 60 mg/kg (subcutaneous injection once a week for 16 weeks) to induce colorectal cancer. PGV-1 and CCA-1.1 at 10 and 20 mg/kg (orally twice a week for 16 weeks) were co-administered with DMH. The WBC count increased in a single DMH group and was countered by co-administration of PGV-1 and CCA-1.1, but no significant differences in RBC. Single DMH treatment for 16 weeks resulted in 80% adenocarcinoma. In contrast, co-administration with PGV-1 and CCA-1.1 suppressed most of the carcinogenic characteristics and symptoms of the pre-malignancy condition. Furthermore, bioinformatics analysis showed that CCA-1.1 has more specific targets than PGV-1, including CDK1, CDK2, MMP3, MMP14, and CYP3A4, which regulate the cell cycle arrest, cancer cell migration, and xenobiotic metabolism, respectively. Interestingly, CCA-1.1 targets CYP3A4, which possibly interrupts DMH metabolism and prevents the initiation of DMH-colorectal carcinogenesis. In conclusion, CCA-1.1 performed better chemopreventive effects against DMH colorectal cancer and might replace PGV-1 to be promoted as a more effective anti-colorectal cancer agent.