CCS1477: A Novel Small Molecule Inhibitor of p300/CBP Bromodomain for the Treatment of Acute Myeloid Leukaemia and Multiple Myeloma

Abstract

E1A binding protein (p300) and CREB binding protein (CBP) are two closely related histone acetyl transferases with oncogenic roles in acute myeloid leukaemia (AML) and multiple myeloma (MM). Here we describe the pre-clinical characterization of CCS1477, an orally bioavailable, potent and selective inhibitor of the bromodomain of p300/CBP and its therapeutic application in AML and MM. CCS1477 binds to p300 and CBP with high affinity (KD=1.3/1.7nM), and selectivity (e.g. KD=222nM; BRD4) in a surface plasmon resonance assay. It is a potent inhibitor of cell proliferation in a panel of 16 AML and 9 MM human cell lines. MM cells were particularly sensitive to CCS1477 with the majority of lines having a GI50 below 100nM. In stromal co-culture assays CCS1477 also inhibited proliferation of primary patient AML blast cells from a range of patients with a variety of molecular subtypes. These anti-proliferative effects were due to a combination of cell cycle arrest (with a decrease of cells in S-phase and an increase in cells in G1/G0) and induction of differentiation, as confirmed by up regulation of selected differentiation markers (e.g. CD11b & CD86) flow cytometric analyses. In xenograft models of AML (MOLM-16) and MM (OPM-2), daily oral dosing with CCS1477 as monotherapy, caused a dose-dependent reduction in tumour growth with regressions observed at the highest dose of 20mg/kg. After cessation of treatment with 20mg/kg CCS1477, there was sustained inhibition of tumour growth for approximately 11 days before re-growth began. The inhibition of tumour growth during drug treatment, was accompanied by significant reduction in tumour expression of MYC and IRF4 by qPCR in the OPM-2 model and in MYC expression in MOLM-16. The effects of CCS1477 were further evaluated in murine models by comparison with candidate standard of care regimens for AML & MM. In the MOLM-16 (AML) model, CCS1477 administered daily by oral gavage (10mg/kg) demonstrated superior tumour growth inhibition by comparison with azacitidine or cytarabine. There was also a significant combination benefit of CCS1477 when administered with these two agents in this model. In OPM-2 MM cells that are sensitive to lenalidomide, CCS1477 was a significantly more potent inhibitor of cell proliferation (GI50 = 5nM; CCS1477 vs. 100nM; lenalidomide). CCS1477 also retains exquisite anti-proliferative potency in MM cells that are either intrinsically resistant to lenalidomide (KMS-11 and RPMI 8226) or in OPM-2 cells that have developed resistance after long-term culture in lenalidomide. CCS1477 shows significant synergy when combined with lenalidomide in OPM-2 cells in vitro and also in an OPM-2 xenograft model in vivo. Significant combination benefit of CCS1477 with vorinostat or velcade is also observed in this xenograft model. These data support the clinical testing of CCS1477 in haematological malignancies, including MM and AML, with a strong pre-clinical rationale for use as monotherapy or in combination with standard of care agents, such as lenalidomide. CCS1477 is currently in Phase I/II clinical trials. Disclosures Brooks: CellCentric Ltd: Employment, Equity Ownership. Somervaille:Novartis: Consultancy. Pegg:CellCentric Ltd: Employment, Equity Ownership.