Title: Poised Fragment Libraries for Atypical Bromodomain Inhibition
Funder: Engineering and Physical Sciences Research Council

Abstract: Melanoma is an increasingly devastating cancer of the skin, whose occurrence is on the rise. It can be treated surgically but long term survival tends to be poor. Often, once detected, it has already metastasised (spread to other parts of the body) and surgical intervention merely removes the original cancer, with the more aggressive form inoperable or intractable (unresponsive) to chemo- or radio- therapies). Thereafter, fatality is inevitable. Fortunately, there are a number of new therapies available for melanoma including "vemurafenib", which is a synthetic molecule acting on a specific mutation (change in a key protein vital for cancer progression, called BRAFV600E (amino acid residue number 600 of the BRAF protein has changed from a valine to a glutamic acid, drastically altering the cancerous nature of the protein)). However, around 50% of melanomas do not carry this particular mutation and therapy is ineffective in these cases. Ipilimumab or pembrolizumab (Keytruda) are newly introduced immunotherapy-based antibody drugs, which cause cells to attack the melanoma by activating the immune system. Many of these drugs are dramatically more effective in combination with others since they can attack the cancer in complementary ways, preventing problematic resistance to the treatments. Indeed, recent clinical trials on the immunotherapy approach have shown very encouraging results with > 2 years survival noted for a number of patients, although side effects in over half of the patients halted their treatment (http://www.bbc.co.uk/news/health-36043882). Hence, despite huge strides in melanoma treatments, the search for new therapies is still vital particularly for melanomas that are not harbouring BRAF-mutations. We have recently discovered a range of molecules that target parts of proteins called bromodomains (BRDs) that are crucial in gene transcription in cancer. One particular BRD, called PHIP, is highly expressed in many melanomas, particularly aggressive types and it has been shown (by De Semir et al., who is a collaborator on this application) that stopping PHIP production biologically, slows down melanoma progression in cells (in vitro), as well as in mice (in vivo). Our recent study has shown, for the first time, how small molecules can inhibit and bind to PHIP(2), one of the forms of PHIP, at the atomic level, by x-ray crystallography. The next stage is to take our original PHIP(2) acting molecules and improve their biological activity and selectivity over other BRDs (there are over 60 of these) in order to be able to use smaller doses, to lower toxicity, side effects and cost. This will act as a proof of principle to show that PHIP(2) inhibition by drug-like molecules is a vital new armoury in our fight against skin cancer. Although a study of this magnitude is unlikely to yield a drug, since this tends to cost a billion or so pounds and take over 12 years, it is expected to contribute to a better understanding of the role of PHIP(2) in melanoma and to a new line of chemical reactions towards biologically active molecules, which may act on either PHIP(2) or on other BRDs. PHIP(2) is an example of an atypical BRD (there are 13 of these vs 48 typical BRDs). Little is known about their inhibition so this study will also have ramifications in atypical BRD inhibition and lead to others studying other atypical BRDs. It will also add to the very important area of epigenetics, a study of inheritable changes of the genome not related to DNA sequence changes, which is an area of science that is en vogue, spanning different branches of science such as environmental factors including diet-related disease and addiction (Brazil, R. Chemistry World, 2016, 34-39).


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS