Poised Fragment Libraries for Atypical Bromodomain Inhibition

黑色素瘤是一种破坏性越来越大的皮肤癌，其发生率正在上升。它可以通过手术治疗，但长期生存往往很差。通常，一旦被检测到，它已经转移（扩散到身体的其他部位），手术干预只是去除了原始癌症，更具侵略性的形式对化疗或放疗无效或顽固（无反应）。幸运的是，目前有许多新的治疗方法可用于黑色素瘤，包括“vemurafenib”，这是一种作用于特定突变的合成分子（改变对癌症进展至关重要的关键蛋白质，称为BRAFV 600 E（BRAF蛋白质的氨基酸残基编号600从缬氨酸变为谷氨酸，大大改变了蛋白质的癌性））。然而，大约50%的黑色素瘤不携带这种特定的突变，并且在这些情况下治疗无效。Ipilimumab或pembrolizumab（Keytruda）是新推出的基于免疫治疗的抗体药物，通过激活免疫系统引起细胞攻击黑色素瘤。这些药物中的许多与其他药物联合使用会更有效，因为它们可以以互补的方式攻击癌症，防止对治疗产生耐药性。事实上，最近关于免疫治疗方法的临床试验已经显示出非常令人鼓舞的结果，对于许多患者注意到> 2年的存活，尽管超过一半的患者的副作用使他们的治疗停止（http：//www.bbc.co.uk/news/health-36043882）。因此，尽管黑素瘤治疗取得了巨大进步，但寻找新的疗法仍然是至关重要的，特别是对于没有携带BRAF突变的黑素瘤。我们最近发现了一系列分子，它们靶向称为溴结构域（BRD）的蛋白质部分，这些蛋白质在癌症基因转录中至关重要。一种特定的BRD，称为PHIP，在许多黑素瘤中高度表达，特别是侵袭性类型，并且已经显示（De Semir等人，他是这项申请的合作者），生物学上阻止PHIP的产生，减缓细胞（体外）和小鼠（体内）中黑色素瘤的进展。我们最近的研究首次通过X射线晶体学在原子水平上展示了小分子如何抑制和结合PHIP（2），PHIP（2）是PHIP的一种形式。下一步是将我们最初的PHIP（2）作用分子与其他BRD相比，提高其生物活性和选择性（有60多个），以便能够使用更小的剂量，以降低毒性，副作用和成本。这将作为一个原则证明，表明药物样分子抑制PHIP（2）是我们对抗皮肤癌的重要新武器。虽然这种规模的研究不太可能产生药物，因为这往往需要花费10亿英镑左右，耗时超过12年，但预计它将有助于更好地理解PHIP（2）在黑色素瘤中的作用，并有助于对生物活性分子进行新的化学反应，这些分子可能作用于PHIP（2）或其他BRD。PHIP（2）是非典型BRD的一个例子（其中有13个，而典型BRD有48个）。关于它们的抑制作用知之甚少，因此这项研究也将对非典型BRD抑制产生影响，并导致其他人研究其他非典型BRD。它还将增加表观遗传学的重要领域，一项与DNA序列变化无关的基因组遗传变化的研究，这是一个流行的科学领域，跨越不同的科学分支，如环境因素，包括饮食相关的疾病和成瘾（巴西，R. Chemistry World，2016，34-39）。

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).