Small molecule inhibition of twin proteins p300 and CBP not only promotes the turnover of key cancer signalling proteins, it also prevents the transcription of key cancer-driving genes. This is a new way to treat multiple cancer types.
CellCentric has developed CCS1477, a first-of-its-kind p300/CBP inhibitor and the first to be evaluated in patients. It is showing early promise. This blog describes the science behind targeting p300/CBP.
p300 and CBP are twin acetyltransferases, enzymes that add acetyl groups to proteins, including histones around which DNA is wrapped. Modifying histones is a central way in which chromatin is physically governed. When histones are condensed together in certain regions, genes in that chromatin area are prevented from being read. Conversely, when chromatin structure is loose, gene transcription is promoted.
Adding acetyl groups to proteins also influences how they are turned over and disposed within a cell. Acetylation prevents ubiquitinylation, which can otherwise trigger proteosomal degradation. p300 and CBP are known to acetylate key signalling proteins involved in cancer progression, including the androgen receptor and its splice variants (AR-SV). Specifically, these are drivers of late stage prostate cancer, with AR-SV being a way tumours adapt, becoming more aggressive and resistant to current therapeutic drugs. Inhibiting p300 and CBP stops AR and its different forms from being protected from degradation, and thus reduces levels of proteins responsible for aggressive cancer progression.
p300 and CBP have another important function, as co-activation proteins. They are cornerstone proteins that aggregate at the start of certain genes and amplify their expression. When p300 and CBP are prevented from binding to other co-activation proteins, the target genes, which include those that can drive cancer, are not expressed.
Thus, a small molecule that inhibits p300 and CBP can not only drive the degradation of key signalling proteins involved in cancer, it can also prevent expression of other oncogenes.
p300 and CBP are complex proteins with multiple pockets on their surface. Predominant is the domain that causes acetylation, the catalytic domain. Multiple small molecule candidate drugs have been developed that bind into this site. Such agents can cause the increased turnover and degradation of proteins involved in cancer, however, these molecules are less likely to have an impact on the gene transcription/co-activation role of p300 and CBP.
p300 and CBP also both have a conserved bromodomain pocket. Bromodomains facilitate protein-protein interactions (they are named after Brahma/brm, the fruit fly gene in which they were initially discovered). A small molecule binding into the p300/CBP bromodomain still impacts p300/CBP’s ability to acetylate, however this effect appears to be discrete, affecting one locus on histones specifically (H3K27).
Perhaps more importantly, p300/CBP bromodomain inhibition has a profound impact on the twin proteins’ roles in activating the transcription of proteins associated with cancer. Small molecules binding into this site significantly lower the expression of well-established cancer-driving genes such as Myc. To date, finding drugs that inhibit Myc has proven challenging. This new approach thus holds the potential to deliver significant benefit to patients with multiple, specific tumour types.
There are over 60 known types of bromodomain pocket on different proteins, many of which have been the focus for small molecule therapy development (e.g. BET inhibitors). The common bromodomains of p300 and CBP are differentiated structurally from others that have been investigated, and it is possible to develop agents that bind into and inhibit p300/CBP without significantly impacting other bromodomains.
As well as the catalytic site and bromodomains, other pockets also exist on p300/CBP, such as the CH1 domain. These may be relevant for drug discovery and therapeutic product development. To date however, targeting the bromodomain appears to deliver the right balance of specificity, mechanistic effects and potential clinical application.
CellCentric’s CCS1477 p300/CBP bromodomain inhibitor is first of its kind. It is in clinical trials, being evaluated in patients with late stage prostate cancer and separately in patients with haematological malignancies. Treating other cancer types where the tumours are driven by p300 or CBP related mechanisms will also be explored.
1. CCS1477 p300/CBP bromodomain inhibition affects the acetylation of histones at H3K27, influencing chromatin structure and what genes can be accessed.
2. CCS1477 p300/CBP inhibition prevents the acetylation of certain signalling proteins (such as AR), which means they can then be ubiquitylated instead, and turned over/destroyed through proteosomal degradation.
3. Possibly most importantly, CCS1477 inhibition stops p300/CBP acting as co-activation factors of key cancer driving genes, such as Myc.