CellCentric's cancer inhibitors
We are developing first-in-class inhibitors of p300 and CBP, paralogue histone acetyl transferase (HAT) proteins that play a critical role in gene regulation in cancer cells.
Our work draws on its foundation of knowledge of epigenetics and its application to novel drug discovery.
CellCentric has discovered and patented potent, highly selective, orally-bioavailable small molecule inhibitors of p300/CBP.
(1) Inhibition of p300/CBP with CellCentric’s compounds leads to the down regulation of the androgen receptor (AR), AR-splice variants and c-Myc in vivo. This AR degradation mechanism of action is directly applicable to the treatment of castrate-resistant prostate cancer (CRPC).
(2) Inhibitors of p300/CBP can also be used selectively against specific cancers. A significant proportion of tumours develop gene mutations, and thus a loss of function, of either p300 or CBP. Such cancer cells then become dependent/addicted to the remaining non-mutated paralogue. When this is inhibited by a drug, synthetic lethality results (cancer cell death). Extensive patient-sample gene analysis supports that p300 and CBP mutations are almost always mutually exclusive. Incidence varies by cancer type, but can be seen in up to 20% of lung cancers (small cell and non-small cell), up to 25% of bladder cancers and up to 30% of blood-related cancers.
Inhibition of p300/CBP has also been shown to affect regulatory T-cells and their suppressive function, thus increasing the ability of the body’s immune system to target tumour cells.
Castrate Resistant Prostate Cancer
Prostate cancer accounts for over 25% of all new male cancers (Cancer Research UK data). Initial treatments for advancing prostate cancer focus on reducing the levels of circulating male hormones (androgens) in the body which the tumour requires for growth. Over time however, the cancer cells are able to circumvent such treatments and can develop into the castrate resistant form of the disease (CRPC). This is lethal with overall survival typically less than 14 months.
The development of CRPC is dependent upon the presence of a functional androgen receptor (AR). CellCentric’s inhibitors lower the levels of the AR in prostate cancer cells. Importantly, they also lower AR-splice variants, a key adaptation that drives resistance to current therapeutic agents, as well as lowering levels of c-Myc.
The company’s approach offers significant additional therapeutic potential, beyond established and newly approved drugs for prostate cancer.
Lung cancer remains the largest cause of cancer death in both men and women. In 15-20% of small cell and non-small cell (NSCLC) lung cancers, gene mutations cause a loss of function of either p300 or CBP. Inhibiting the remaining paralogue drives cancer cell death, known as synthetic lethality. Such mutations are a distinct subset from others, such as ALK fusions. Thus this offers a distinct additional opportunity to specific phenotype-driven treatment.
There are over 75,000 new cases of bladder cancer in the US every year, with over 16,000 deaths in 2016 (NIH data). Prevalence is slightly higher in men compared to women. Loss of function somatic gene mutation rates in p300 and CBP bladder cancer biopsies have been reported at 13.8% and 11.2% respectively; 25.0% in total, a significant proportion of sufferers overall.
Loss of function by gene mutation of either p300 or CBP occurs in multiple other types of cancer, including many haematological disorders including lymphoma and leukaemia.
Histone methyltransferase target
CellCentric has previously developed, partnered and then licensed a histone methyltransferase (HMT) drug discovery programme to Takeda Pharmaceuticals.
CellCentric’s early advantage came from working with over 25 leading laboratories identifying epigenetic processes and targets. The company was originally founded with one of the pioneers of epigenetics, Prof Azim Surani FRS CBE, at the University of Cambridge.
CellCentric continues to collaborate with a number of academic research groups on p300/CBP biology and mechanism of action, in relation to the potential breadth of therapeutic use of the company’s lead candidate drug, CCS1477.