Rational small molecule drug discovery and development requires a clear line of sight between biology, chemistry and clinical application. CellCentric’s CCS1477 programme targets specific gene and protein regulatory mechanisms of action with a highly potent, selective small molecule inhibitor. In this blog we describe how this then translates to specific applications in cancer, addressing significant clinical unmet needs.
p300 and CBP are twin histone acetyltransferase proteins. They have several actions within a cell, all associated with a common consequence, the control of gene expression and cell signalling. Unchecked, these processes have a key role in the progression of multiple cancer types.
Late stage, aggressive prostate cancer is exacerbated by androgen receptor (AR) signalling. In the last decade a series of drugs have emerged that target AR, so called second generation anti-hormonal drugs including abiraterone (Zytiga) and enzalutamide (Xtandi). These are widely used, multi-billion dollar drugs, extending the lives of thousands of patients. However, over time tumours become resistant to these drugs, including through mutations to AR and the generation of AR-splice variants. Both of these continue to drive proliferation of cancer cells which are no longer responsive to the anti-hormonal drugs.
CellCentric’s drug, CCS1477, inhibits the conserved bromodomain of p300 and CBP. The consequence of this is to not only impact the levels and function of AR, but also of mutated AR and AR-splice variants. As a result the drug should deliver benefit to patients that are either inherently or have become resistant to, second generation anti-hormonal drugs. CellCentric is currently testing CCS1477 in clinical trials involving patients whose tumours have progressed having been treated with either abiraterone or enzalutamide. These patients have few alternative treatment options, a major clinical unmet need. The company will also test its effects in combination with these two drugs to see if that has a more profound, synergistic effect.
p300/CBP inhibition also impacts the expression of c-Myc (and its related protein n-Myc), a transcription factor that is often over-expressed in cancer. CellCentric has shown both in models and in human samples, that treatment with CCS1477 can dramatically reduce levels of c-Myc in cells.
Many blood cancers (haematological malignancies) have been shown in laboratory screens to be particularly sensitive to CCS1477. This is particularly the case for multiple myeloma, but also acute myeloid leukaemia as well as certain lymphomas. Some of this will be because of the impact on c-Myc. But it is also because p300/CBP inhibition impacts another transcription factor, IRF4 which is a particularly important driver in multiple myeloma. CCS1477 is currently at the start of clinical trials evaluating its effectiveness for a range of haematological malignancies. Patients being tested all have relapsed disease, unresponsive to existing treatments. In most cases they have limited weeks and months to live. Thus CCS1477, if proven effective, could make a very significant difference.
Importantly, CellCentric’s drug is administered as an oral capsule, taken once or twice a day. It is differentiated from many other new products being developed to treat blood cancers, which require lengthy intravenous administration and significant hospital time.
As patients are treated in the healthcare system, their tumours are often profiled for gene and protein expression. This can highlight tumours that are dependent on certain driver mutations or other genetic changes. This includes tumours that appear to be fuelled by amplification of the AR or c-Myc genes. Given that p300/CBP inhibition impacts these factors specifically, it makes sense to explore if they can be treated with CCS1477. CellCentric has recently gained permission from the UK’s medicines regulatory authority, the MHRA, to specifically treat AR+ and c-Myc+ tumours with CCS1477, irrespective of cancer type.
Certain cancer types gain mutations across their genomes, at high frequency, including the genes encoding p300 or CBP. This often leads to one of the twin proteins becoming inactive. In this case, the tumour becomes highly dependent on the other non-mutated, active twin. This is so called synthetic, or paralogue lethality. Bladder cancers, small cell lung cancers and certain lymphomas (e.g. DLBCL) have a high percentage (>20%) of loss of function mutations in either p300 or CBP. These should then be sensitive to CCS1477 which inhibits both proteins. This has proven the case in majority of tumour samples tested in the lab. CellCentric is now applying this to patients in clinical studies.
CCS1477, is a highly potent and specific small molecule drug that is backed by deep understanding of its biological effects. It is now in clinical trials exploring its potential to treat multiple cancer types. It delivers on the clear line of sight: biology-chemistry-clinical applications.