Poised Fragment Libraries for Atypical Bromodomain Inhibition

黑色素瘤是一种日益严重的皮肤癌症，其发病率呈上升趋势。它可以通过手术治疗，但长期存活率往往很低。通常情况下，一旦发现，它已经转移（扩散到身体的其他部位），手术干预只是去除原来的癌症，更严重的形式不能手术或难以治疗（对化疗或放疗无反应）。此后，死亡是不可避免的。幸运的是，目前有许多治疗黑色素瘤的新疗法，包括“vemurafenib”，这是一种合成分子，作用于一种特定的突变（一种对癌症进展至关重要的关键蛋白质BRAFV600E的变化（BRAF蛋白的氨基酸残基编号600从缬氨酸变成了谷氨酸，彻底改变了蛋白质的癌变性质））。然而，大约50%的黑色素瘤不携带这种特殊的突变，治疗在这些情况下是无效的。Ipilimumab或pembrolizumab （Keytruda）是新推出的基于免疫治疗的抗体药物，通过激活免疫系统导致细胞攻击黑色素瘤。这些药物中有许多与其他药物联合使用会显著地更有效，因为它们可以以互补的方式攻击癌症，防止对治疗产生问题的耐药性。事实上，最近关于免疫疗法的临床试验显示了非常令人鼓舞的结果，许多患者的生存期达到了50年，尽管超过一半的患者因副作用而停止了治疗（http://www.bbc.co.uk/news/health-36043882）.Hence)，尽管黑色素瘤治疗取得了巨大进展，但寻找新的治疗方法仍然至关重要，特别是对于没有braf突变的黑色素瘤。我们最近发现了一系列分子，这些分子针对的是在癌症基因转录中起关键作用的称为溴结构域（BRDs）的蛋白质部分。一种特殊的BRD，称为PHIP，在许多黑色素瘤中高度表达，特别是侵袭性类型，并且已经证明（由De Semir等人，他是该应用的合作者），从生物学上停止PHIP的产生，可以减缓细胞（体外）和小鼠（体内）黑色素瘤的进展。我们最近的研究首次表明，通过x射线晶体学，小分子如何在原子水平上抑制和结合PHIP(2)， PHIP的一种形式。下一阶段是采用我们最初的PHIP(2)作用分子，并提高它们比其他brd（有超过60种）的生物活性和选择性，以便能够使用更小的剂量，降低毒性，副作用和成本。这将作为一个原理证明，表明药物样分子对PHIP(2)的抑制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，因为这往往花费10亿英镑左右，需要12年以上的时间，但它有望有助于更好地了解PHIP(2)在黑色素瘤中的作用，并为可能作用于PHIP(2)或其他brd的生物活性分子的新化学反应做出贡献。PHIP(2)是一个非典型BRD的例子（其中有13个与48个典型BRD）。对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。它还将增加非常重要的表观遗传学领域，研究与DNA序列变化无关的基因组的可遗传变化，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，包括饮食相关疾病和成瘾（巴西，R.化学世界，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).