Discovery of a potent and selective peptide inhibitor with d-amino acids targeting the BRD4 ET domain for renal cancer therapy

Renal cancer is a highly aggressive tumor that poses a serious threat to human health. BRD4, as an important epigenetic regulator, is tightly associated with the development of renal cancer. Given the unique biological stability of d-amino acids, they have shown great potential for application in the field of cancer therapy. Currently, there are no reports on d-amino acid inhibitors targeting the ET domain of BRD4. Herein, we discovered a peptide inhibitor containing d-amino acids (BEP-2) targeting the BRD4 ET domain through virtual screening. BEP-2 showed an excellent binding affinity for BRD4 (K_d = 0.45 ± 0.03 nM). MD simulations demonstrate that BEP-2 can stably bind to the BRD4 ET domain. Moreover, BEP-2 displayed good inhibitory activity against 786-O and ACHN renal cancer cells and maintained high stability in serum. Additionally, BEP-2 inhibited the growth of 786-O cell xenograft tumors in nude mice. In summary, these data imply that BEP-2 is a promising antitumor drug that offers new perspectives for the treatment of renal cancer.