Clinical Programme

Haematological Cancers

Haematological malignancies, including multiple myeloma (MM), acute myeloid leukaemia (AML) and certain lymphomas, are regulated in part by p300/CBP.

In multiple myeloma, the IRF4 and MYC transcription factors play a central role in the development and progression of the disease. In an in vivo xenograft model of multiple myeloma (OPM2), inobrodib stops tumours growing and in some cases, causes them to regress. This is accompanied by a very significant reduction in the expression of the IRF4 and MYC transcription factors. Inobrodib may be of particular benefit in patients with multiple myeloma offering a more selective approach to targeting these key oncogenic drivers.

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Patients with AML who have relapsed or are refractory to initial therapy, or are elderly and not deemed suitable for standard intensive treatment, currently have few remaining treatment options and these offer limited survival benefit and are often associated with an unfavourable safety profile.

P300/CBP interacts with many different oncogenes or fusion proteins to regulate target genes that are involved in the self-renewal of haematopoetic stem/progenitor cells and growth of leukaemic cancers. Inobrodib inhibits the proliferation of patient derived AML cells through cell cycle arrest and with an accompanying increase in markers of cell differentiation. Inobrodib may be of particular benefit in patients who have failed initial treatment, through targeting of aberrant self-renewal linked to disease relapse.

Follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL) are the two most common subtypes of non-Hodgkin lymphoma (NHL) and are frequently characterised by having mutations and deletions in CBP and to a lesser extent, p300. Tumours that have these mutations are more sensitive to inobrodib compared with their non-mutated counterparts, so there is a strong rationale for the therapeutic targeting of p300/CBP in NHL tumours, particularly those with loss of function CBP mutations.