NEO2734: A novel potent oral dual BET and P300/CBP inhibitor

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: 429PCell lineTissue TypeIC50 (μM) (72h)NEO2734iBET762CisplatinT24Bladder0.597.21.4Molt-4Blood0.562.40.49KHYG-10.181.10.46Raji0.321.80.91BT474Breast1.7> 1049SK-BR-30.76> 101.5ColorectumDLD-10.67> 102.1SW11160.86> 105.9Hep3BLiver0.89> 103.6SNU-3540.47> 107.6OvarySW6260.79> 102.3SW7560.83> 101.2PancreasPL451.2> 102.2SW19902.8> 101.822Rv1Prostate0.61> 102.4LNCaP clone FGC0.240.998.7VCAP0.170.7933SK-MEL-28Skin3.9> 107.5SK-MEL-50.96> 104.1 Open table in a new tab 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. Legal entity responsible for the study: Neomed Therapeutics 1 Ltd. Funding: Neomed Therapeutics 1 Ltd. Disclosure: F. Giles: Consultant: Neomed Therapeutics 1. B. Brown: Employee: Neomed Institute. All other authors have declared no conflicts of interest.