Inhibiting the conserved bromodomain of p300 and CBP

CCS1477: a first-in-class small molecule, administered as an oral capsule, to treat multiple specific cancer types

Targeting twin acetyltransferases p300 and CBP

p300 and CBP are paralogue (twin) histone acetyltransferases (HATs) that impact the expression of cancer driving genes, as well as key cancer-related signalling pathways.

The function of p300/CBP can be inhibited by specific small molecules binding into pockets on the surface of the proteins. CellCentric has focused on targeting the bromodomain pocket. Binding into here affects p300/CBP’s ability to act as transcription co-activation factors of cancer associated genes such as MYC and IRF4.

p300/CBP inhibition additionally prevents the acetylation of important signalling proteins, which means they can then be ubiquitinylated instead, and turned over/destroyed through proteosomal degradation.

Targeting the bromodomain of p300 and CBP

Developing inhibitors to histone acetyltransferases has been of interest for a number of years. Targeting the active HAT catalytic site of p300/CBP has proven challenging.

CellCentric instead chose to focus on targeting the conserved bromodomain pockets of p300/CBP. This can also profoundly impact p300/CBP function, and differently from inhibiting the HAT catalytic domain. Other pockets on the proteins can also be targeted (such as CH1). To date it seems that binding into the bromodomain gives the best balance of selectivity, potency and desired effects.

CCS1477 as a drug

CCS1477 is the first inhibitor of p300/CBP to be evaluated in clinical trials. The active ingredient is readily manufactured by a short synthetic route, formulated as an orally-available drug, prepared in capsules. For haematological malignancy applications in particular, oral administration is a key advantage. The drug product is stable and can be stored at room temperature.

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