Bcl-2 phase I clinical candidate
S55746 is an orally bioavailable, Bcl-2-selective inhibitor that spares Bcl-xL-dependent cells such as platelets, and progressed to phase I.
The Challenge
Escape from apoptosis is one of the major hallmarks of cancer cells. The Bcl-2 gene family encodes pro-apoptotic and anti-apoptotic proteins that are key regulators of the apoptotic process. Overexpression of the pro-survival member Bcl-2 is a well-established mechanism contributing to oncogenesis and chemoresistance in several cancers, including lymphoma and leukaemia. Bcl-2 has therefore become an attractive target for therapeutic intervention.
The Science
Structure-guided design delivered S55746 (also known as BCL201), a novel, orally bioavailable, potent and Bcl-2-selective inhibitor that occupies the hydrophobic groove of Bcl-2.
The selectivity profile of S55746 demonstrates no significant binding to Mcl-1 or BFL-1 (Bcl-2A1/A1), and poor affinity for Bcl-xL. Accordingly, S55746 has no cytotoxic activity on Bcl-xL-dependent cells, such as platelets.
In a panel of haematological cell lines, S55746 induces hallmarks of apoptosis including externalisation of phosphatidylserine, caspase-3 activation and PARP cleavage. Ex vivo, S55746 induces apoptosis in the low nanomolar range in primary chronic lymphocytic leukaemia and mantle cell lymphoma patient samples.
Administered by oral route daily in mice, S55746 demonstrated robust anti-tumour efficacy in two haematological xenograft models with no weight loss and no change in behaviour. Taken together, these data demonstrate that S55746 is a novel, well-tolerated BH3-mimetic targeting the Bcl-2 protein selectively and potently.
X-ray crystal structure of S55746 in complex with Bcl-2 (PDB: 6GL8).
Key Takeaways
- Orally bioavailable, potent and Bcl-2-selective inhibitor taken to phase I
- No cytotoxic activity against Bcl-xL-dependent cells such as platelets
- Low nanomolar apoptosis induction in primary CLL and mantle cell lymphoma patient samples
- Robust xenograft efficacy on daily oral dosing with no weight loss
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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