Synthesis and biological evaluation of a novel c-Myc inhibitor against colorectal cancer via blocking c-Myc/Max heterodimerization and disturbing its DNA binding

c-Myc is a transcription factor that is aberrantly expressed in the majority of human cancers. Recent studies unveiled that abnormal expression of c-Myc protein is involved in the development of colorectal cancer (CRC). Previously, we reported a novel phenoxy-N-phenylaniline derivative A-42 that can inhibit c-Myc protein and the growth of different CRC cancer cells potently. To look for a better candidate, the structure-activity relationship (SAR) of A ring, D ring and the linker between A and B rings of A-42 was investigated, and a series of compounds were synthesized. Among them, compound B13 was identified as the most active c-Myc inhibitor with cyto-toxicity activity against HT29 and HCT116 cells at IC50 0.29 mu M and IC50 0.64 mu M, respectively, which is superior to that of A-42. According to the bioassays, compound B13 not only can suppress CRC cells proliferation and migration, but also inhibit the binding of c-Myc/Max dimer to DNA, which further interfere with the expression of the relevant proteins of apoptosis pathway. Furthermore, B13 could inhibit HT29 tumor growth in xenograft mouse models potently with tumor growth inhibitions (TGIs) up to 65.49% at dose of 40 mg/kg, which is su-perior to A-42 (55.82%, 40 mg/kg). Overall, B13 may potentially serve as an effective CRC therapy via blocking c-Myc/Max binding with DNA.