Mcl-1 in vivo active inhibitor
An NMR fragment screen and structure-guided design delivered S63845, a specific, high-affinity Mcl-1 inhibitor with single-agent anti-tumour activity in vivo.
The Challenge
Avoidance of apoptosis is critical for the development and sustained growth of tumours. The pro-survival protein myeloid cell leukaemia 1 (Mcl-1) is over expressed in many cancers, but the development of small molecules targeting this protein that are amenable for clinical testing has been challenging.
The Science
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.
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.
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.
X-ray crystal structure of S63845 in complex with Mcl-1 (PDB: 5LOF)
Key Takeaways
- Fragment hit developed into a specific, high-affinity Mcl-1 binder
- Kills Mcl-1-dependent myeloma, leukaemia and lymphoma cells via BAX/BAK-dependent apoptosis
- Single-agent anti-tumour activity in vivo with an acceptable safety margin
- Published in Nature — the highest-profile result in the Vernalis portfolio
Service Areas
Work with us
Vernalis has collaborated with a wide range of partners to enable some of the most challenging therapeutic targets. Present and past collaborators include Servier, Pierre Fabre, Genentech and Lundbeck. Vernalis can support programs with DEL and fragment-based technologies through to establishing full drug discovery programmes for our partners.
Our track record is built on innovation and success in enabling drug discovery and identifying clinical candidates for a wide variety of therapeutic targets.
Research Director and Joint Site Lead
James Murray PhD
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