Inhibiting the conserved bromodomain of p300 and 

CCS1477: a first-in-class small molecule to treat prostate and other cancers

  • 80,000+

    Men with prostate cancer

    could ultimately benefit from CCS1477 annually

  • 20,000+

    Patients with blood cancers

    multiple myeloma, AML, lymphomas

  • 50+

    Epigenetic-related targets

    investigated over time by the CellCentric team

  • 1

    Drug prioritised, advanced

    CCS1477 in the clinic, for multiple indications

Targeting histone acetyltransferases p300 and CBP

p300 and CBP are paralogue (twin) histone acetyltransferases (HATs) that are important in the regulation of cell fate. They acetylate other proteins as well as histones, which are important in the regulation of gene expression. The acetylation of proteins can also increase their longevity within cells, as acetylation blocks poly-ubiquitinylation, and thus protein proteosomal degradation (turnover and destruction). Thus, CCS1477 as an inhibitor of acetylation, can lead to increased turnover of specific proteins, including the androgen receptor and its splice variants.

p300/CBP also act as transcription coactivation factors, assembling with other proteins to cause the initiation of expression of specific genes.

Targeting the bromodomain of p300 and CBP

Developing inhibitors to histone acetyltransferases has been of interest for a number of years. Targeting the active catalytic site of p300/CBP has proven challenging, including because of a lack of specificity. In terms of specificity compared to effects on other HATs.

CellCentric chose to focus on the conserved bromodomains of p300/CBP, another pocket on the twin proteins that also can be targeted and blocked with small molecules, profoundly affecting p300/CBP function. This is likely to disrupt their role as key scaffolding proteins.

CCS1477, a bromodomain inhibitor

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

CCS1477 is a novel small molecule discovered and developed by CellCentric. The compound is highly selective for the specific conserved bromodomains of p300 and CBP. Cancer cells that are resistant to BET inhibitors (for instance JQ1, OTX-015, iBET-151), remain highly sensitive to CCS1477.

CCS1477 as a drug

CCS1477 is a highly specific small molecule inhibitor of p300/CBP, exquisitely potent against certain cancer cell types. It binds reversibly to the bromodomain of p300 and CBP, rather than reacting with the protein to become permanently attached. It is readily synthesised by a short synthetic sequence and formulated as an orally-available drug, prepared in capsules. It can be stored for an extended period prior to use.