Differentiation

CCS1477, a differentiated and highly selective bromodomain inhibitor

There are over 60 different bromodomains on cellular proteins, many of which constitute potential drug targets. Multiple BET inhibitors are in clinical trials currently, for instance targeting the BRD4 bromodomain for oncology applications.

CCS1477 is a novel small molecule discovered and developed by CellCentric.

The compound is highly selective for the specific conserved bromodomain of p300 and CBP. Cancer cells that have become resistant to BET inhibitors (for instance JQ1, OTX-015, iBET-151), remain highly sensitive to CCS1477. CCS1477 also affects the expression of far fewer genes than BET inhibitors, whilst having a profound anti-tumour effect.

CCS1477 affects less/different genes than JQ1 in 22Rv1 cells

In prostate cancer, CCS1477, unlike other agents, down-regulates not just the androgen receptor (AR), but also AR splice variants. These are important in the innate or acquired resistance to existing treatments.

Certain haem cancers are highly susceptible to p300/CBP inhibition, and particularly in combination with IMiD agents, where certain pre-clinical models have shown that tumour cells can be eliminated. Being an orally delivered product, it has significant advantages over other new haem treatments in development that can require extended intravenous infusion.

CCS1477 has an unusual duration of effect in pre-clinical models. Tumour stasis is sustained far beyond cessation of drug administration, even though there is no drug remaining in circulation. Tumours are in effect, reprogrammed to a degree.

By targeting the bromodomain of p300/CBP, CCS1477 has a different efficacy and tolerability profile from other agents in discovery that target the catalytic HAT or CH1 domain.

CS1477 retains activity in JQ1/BETi resistant 22Rv1 cell-line

There are other drugs that target bromodomains. However, CCS1477 is highly specific for p300/CBP and thus has a different profile to BET inhibitor drugs. It is active in cancer cell lines that are resistant to BET inhibitors (such as JQ1, OTX-15, iBET-151).

In breadth-of-efficacy cell panel testing, CCS1477 has a very specific effect on clusters of cancer types, rather than being generally cytotoxic.

Unlike many other cancer agents in development, CCS1477 has the potential to be used as a monotherapy for multiple applications, not just in combination with existing agents.