A first-in-class oral anti-cancer with a new mechanism of action - targeting twin tumour drivers, p300/CBP

Inobrodib is a p300/CBP inhibitor that inhibits a number of known, yet elusive to treat oncogenes, to deliver improved treatments for people with cancer

A highly differentiated, first-in-class compound with a novel mechanism of action, inobrodib can stop and reverse cancer growth in some of the most difficult to treat indications (e.g. metastatic Castration Resistant Prostate Cancer). Its versatile and can treat both solid tumours (e.g., prostate) and blood (haematological) cancers and allows for combination treatment with standard of care drugs and other novel therapies. It's also easy to administer, a small molecule oral formulation that can be taken in the comfort of the patient’s own home, avoiding long appointments in hospital. Transitioning to Phase 2 clinical trials

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.

Inobrodib is a small molecule inhibitor that uniquely targets and inhibits the functionality of p300/CBP through binding to the conserved bromodomain. Inobrodib binding affects p300/CBP’s ability to:

Act as transcription co-activation factors of cancer associated genes such as MYC, AR (and variants), IRF4 and PR1/PD-L1.

Acetylate important signalling proteins, which means they can then be ubiquitinylated instead, and destroyed through proteasomal degradation.

Targeting the bromodomain of p300 and CBP

Developing inhibitors to histone acetyltransferases (HAT) 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.

Inobrodib is the first orally available drug of its kind

Inobrodib 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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