CellCentric’s novel p300/CBP inhibitor, CCS1477 advancing to the clinic

Posted on February 16th 2017

CellCentric has developed a potent, selective, orally bioavailable small molecule inhibitor of p300/CBP. These targets are key regulators of cancer cells, and specifically play a critical role in the progression of the aggressive form of prostate cancer. Key pre-clinical efficacy data on CellCentric’s compound CCS1477 is presented today at GU-ASCO, Orlando (1).

GU-ASCO poster 2017: http://www.cellcentric.com/gu-asco-poster-2017

Castrate resistant prostate cancer (CRPC) remains a significant unmet need, despite recent advances including the adoption of new agents such as Enzalutamide and Abiraterone. CRPC is driven by functional androgen receptor (AR) proteins, and modified AR-splice variants that emerge (2).

Data shared today shows that CellCentric’s candidate drug CCS1477 lowers AR and AR-splice variants, as well as the key cancer regulator c-Myc, causing complete inhibition of prostate tumour growth in vivo (22Rv1 xenograft). PSA levels are completely suppressed, a well-known biomarker of prostate cancer, as well as AR-regulated genes such as TMPRSS2. CellCentric is now advancing CCS1477 in to the clinic.

p300/CBP are twin (paralogue) proteins that act as transcriptional co-activators, which help govern which genes are used or not used within cells. They are also active acetyl transferases that play a role in turnover of proteins within cells, including AR. CellCentric’s drug compound CCS1477 binds to a common conserved bromodomain of p300 and CBP.

Separate from prostate cancer, certain tumours develop loss of function mutations in either p300 or CBP. It has been shown that when this occurs, the cancer cell becomes dependent on the non-mutated paralogue (3). Inhibition of the non-mutated protein can drive cancer cell death – known as synthetic lethality.

Specific p300 and CBP mutations can be detected to identify patients that could benefit from a targeted drug such as CCS1477. This opportunity represents up to 20% of lung cancer sufferers (both small cell and non-small cell) and 25% of patients with bladder cancer, as well as up to 30% of haematological cancers. These are significant areas of unmet clinical need.

Dr Neil Pegg, CellCentric’s Research Director, commented: ‘Developing small molecule inhibitors to histone acetyl transferases such as p300/CBP, has been notoriously difficult. However, by targeting the conserved bromodomains, we have developed compounds that are highly potent and specific, and which also have key drug-like properties, including a meaningful therapeutic window and appropriate pharmacokinetics.’

CellCentric is a privately-held biotech company based in Cambridge, UK. It originally started as a spin-out of the University, concentrating on epigenetic-related mechanisms by which cells change function and fate. When such mechanisms go awry, disease can result, notably cancer. The company has investigated over 50 potential cancer targets, before focusing on histone acetyltransferases p300/CBP. CellCentric benefited from Innovate UK support to progress its R&D.

The company operates with specialist research partners across the globe, as well as leading academic and clinical leaders including Prof Karen Knudsen, Director, NCI-designated Sidney Kimmel Cancer Center; Chair, Dept. of Cancer Biology at Thomas Jefferson University, who co-authored the GU-ASCO poster presented today.

CellCentric is scheduled to start testing CCS1477 in patients at the turn of 2017-2018, both in the UK and USA. The company has recently appointed Karen Clegg, formerly of AstraZeneca, as Clinical Operations Director to help lead these efforts.

GU-ASCO poster 2017: http://www.cellcentric.com/gu-asco-poster-2017

1. GU-ASCO: 2017 Genitourinary Cancer Symposium, Orlando 16-18 Feb, 2017.

2. Antonarakis et al., (2014) NEJM, 371, 1028-38.

3. Ogiwara et al., (2016) Cancer Discovery 6(4):430-45.

About CellCentric

CellCentric is a biotechnology company developing novel therapeutic products, based on its knowledge of epigenetics. The company was co-founded with Prof Azim Surani FRS CBE of University of Cambridge, and one of the earliest pioneers in the space.

CellCentric has identified and investigated multiple potential drug targets associated with epigenetic regulation, and has carried out early drug discovery on six. One of these, an arginine methyltransferase programme was licenced to Takeda Pharmaceuticals. The company’s own lead programme is the development of first-in-class inhibitors of p300/CBP histone acetyltransferases. These have potential for the treatment of the aggressive form of prostate cancer (CRPC), as well as other cancers through a synthetic lethality mechanism.

About Innovate UK

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