Myeloid cell leukemia 1 (Mcl-1) – in vivo active inhibitor
Avoidance of apoptosis is critical for the development and sustained growth of tumours. The pro-survival protein myeloid cell leukaemia 1 (Mcl-1) is overexpressed in many cancers, but the development of small molecules targeting this protein that are amenable for clinical testing has been challenging.
An NMR-based fragment screen and subsequent structure-guided drug discovery yielded S63845, a small molecule that specifically binds with high affinity to the BH3-binding groove of Mcl-1.
X-ray crystal structure of S63845 in complex with Mcl-1 (PDB: 5LOF)
Mechanistic studies demonstrate that S63845 potently kills Mcl-1-dependent cancer cells, including multiple myeloma, leukaemia and lymphoma cells, by activating the BAX/BAK-dependent mitochondrial apoptotic pathway. In vivo, S63845 shows potent anti-tumour activity with an acceptable safety margin as a single agent in several cancers. Moreover, Mcl-1 inhibition, either alone or in combination with other anti-cancer drugs, proved effective against several solid cancer-derived cell lines. These results point towards Mcl-1 as a target for the treatment of a wide range of tumours.