Probing the AFF4–CCNT1 protein–protein interaction using a metal–organic conjugate for treating triple-negative breast cancer

The interaction between AFF4 and the P-TEFb cyclin T1 (CCNT1) subunit is linked with various human cancers, including triple-negative breast cancer (TNBC). However, the development of chemical probes targeting the AFF4–CCNT1 protein–protein interaction (PPI) has been hindered by the lack of available inhibitors for this interaction. In this study, we conducted a virtual screening campaign to identify inhibitors of the AFF4–CCNT1 protein–protein interaction (PPI) from natural product analogues, and the hits were used to develop the conjugate metal complex 1 as a probe for TNBC. Complex 1 bound to CCNT1 and reduced oncogene MYC transcription and the proliferation, metastasis, and stem-like ability of TNBC cells. It also exhibited desirable photophysical properties for imaging CCNT1 and could distinguish cancer cells from normal cells. In a murine model of breast cancer, complex 1 displayed strong antiproliferation activity. To our knowledge, complex 1 is the first probe that possesses high selectivity and imaging ability for CCNT1, with the ability to suppress TNBC cell stem-like abilities and tumor growth through targeting the AFF4–CCNT1 interaction in vitro and in vivo.