Abstract 2510
Background
The Bromodomain (BRD) and Extra-Terminal domain (BET) family of proteins are key regulators of epigenetic control. Modulation of the BET family is a developmental therapeutics priority. Cyclic AMP response element binding protein (CREB)-binding protein (CBP) and E1A interacting protein of 300 kDa (EP300 or P300) are highly homologous BRD-containing transcriptional co-activators and are validated oncology targets. We have developed a series of potent dual inhibititors of BET-CBP/P300 with NEO2734 and NEO1132 as lead clinical candidates.
Methods
NEO2734 was profiled against the BET inhibitor iBET762 in cellular assays and in multiple human cancer xenograft models including castrate resistant prostate cancer (CRPC) (Vcap) and colon cancer (MC38).
Results
NEO2734 antiproliferative activity against a variety of solid tumor cell lines (Table). In a MDA-MB-231 Triple negative breast cancer cell line NEO2734 was more efficient at killing the cancer cells (85%) than a range of non-dual BET inhibitors which killed up to 50% of the cancer cells. NEO2734 has major activity at 10mg/kg (p.o.) in both CRPC and a colon cancer xenograft model whereas iBET762 has minimal activity at 30mg/kg (p.o.) both dosed once daily for 18 days. In the CRPC (Vcap) xenograft, mice were treated by oral gavage with NEO2734 (10mg/kg, and 15mg/kg) and the reference compound iBET762 (30mg/kg) for 18 days. In this model, NEO2734 led to potent tumor regression in a dose dependent manner. Much weaker activity was observed for iBET-762 at either 30 mg/kg. The antitumor activity correlated well with the reduction of PSA. The colon cancer xenograft was carried out in Syngeneic mice and the activity was compared with iBET762, anti-CTLA4 and anti-PDL1. NEO2734 was active at 10mg/kg (p.o.), as seen with the anti-PDL1 and superior to the anti-CTLA4 and iBET762.Table: 429P
| Cell line | Tissue Type | IC50 (μM) (72h) | ||
|---|---|---|---|---|
| NEO2734 | iBET762 | Cisplatin | ||
| T24 | Bladder | 0.59 | 7.2 | 1.4 |
| Molt-4 | Blood | 0.56 | 2.4 | 0.49 |
| KHYG-1 | 0.18 | 1.1 | 0.46 | |
| Raji | 0.32 | 1.8 | 0.91 | |
| BT474 | Breast | 1.7 | > 10 | 49 |
| SK-BR-3 | 0.76 | > 10 | 1.5 | |
| Colorectum | ||||
| DLD-1 | 0.67 | > 10 | 2.1 | |
| SW1116 | 0.86 | > 10 | 5.9 | |
| Hep3B | Liver | 0.89 | > 10 | 3.6 |
| SNU-354 | 0.47 | > 10 | 7.6 | |
| Ovary | ||||
| SW626 | 0.79 | > 10 | 2.3 | |
| SW756 | 0.83 | > 10 | 1.2 | |
| Pancreas | ||||
| PL45 | 1.2 | > 10 | 2.2 | |
| SW1990 | 2.8 | > 10 | 1.8 | |
| 22Rv1 | Prostate | 0.61 | > 10 | 2.4 |
| LNCaP clone FGC | 0.24 | 0.99 | 8.7 | |
| VCAP | 0.17 | 0.79 | 33 | |
| SK-MEL-28 | Skin | 3.9 | > 10 | 7.5 |
| SK-MEL-5 | 0.96 | > 10 | 4.1 |
Conclusions
NEO2734, a novel oral potent dual inhibitor of BET and CBP/P300, has significant pre-clinical activity in a spectrum of human solid tumors. Clinical studies are in preparation.
Clinical trial identification
Legal entity responsible for the study
Neomed Therapeutics 1 Ltd.
Funding
Neomed Therapeutics 1 Ltd.
Editorial Acknowledgement
Disclosure
F. Giles: Consultant: Neomed Therapeutics 1. B. Brown: Employee: Neomed Institute. All other authors have declared no conflicts of interest.
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