Poised Fragment Libraries for Atypical Bromodomain Inhibition
用于非典型布罗莫结构域抑制的平衡片段文库
基本信息
- 批准号:EP/P026990/1
- 负责人:
- 金额:$ 54.64万
- 依托单位:
- 依托单位国家:英国
- 项目类别:Research Grant
- 财政年份:2017
- 资助国家:英国
- 起止时间:2017 至 无数据
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
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).
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)。人们对它们的抑制知之甚少,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非常重要的领域,即研究与DNA序列变化无关的基因组遗传变化,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,包括饮食相关的疾病和成瘾(巴西,R. Chemistry World,2016,34-39)。
项目成果
期刊论文数量(10)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Expanding the Repertoire of Low-Molecular-Weight Pentafluorosulfanyl-Substituted Scaffolds.
- DOI:10.1002/cmdc.202100641
- 发表时间:2022-04-05
- 期刊:
- 影响因子:3.4
- 作者:
- 通讯作者:
Synthesis and Biological Investigation of (+)-JD1, an Organometallic BET Bromodomain Inhibitor
- DOI:10.1021/acs.organomet.9b00750
- 发表时间:2020-02-10
- 期刊:
- 影响因子:2.8
- 作者:Hassell-Hart, Storm;Runcie, Andrew;Spencer, John
- 通讯作者:Spencer, John
Synthesis of a Thiazole Library via an Iridium-Catalyzed Sulfur Ylide Insertion Reaction.
- DOI:10.1021/acs.orglett.2c02996
- 发表时间:2022-11-04
- 期刊:
- 影响因子:5.2
- 作者:Hassell-Hart, Storm;Speranzini, Elisa;Srikwanjai, Sirihathai;Hossack, Euan;Roe, S. Mark;Fearon, Daren;Akinbosede, Daniel;Hare, Stephen;Spencer, John
- 通讯作者:Spencer, John
Probing BRD Inhibition Substituent Effects in Bulky Analogues of (+)-JQ1
探讨 ( )-JQ1 的大体积类似物中 BRD 抑制取代基效应
- DOI:10.1002/hlca.202000214
- 发表时间:2021
- 期刊:
- 影响因子:1.8
- 作者:Hassell-Hart S
- 通讯作者:Hassell-Hart S
Room-Temperature Cu(II) Radical-Triggered Alkyne C-H Activation.
- DOI:10.1021/jacsau.1c00310
- 发表时间:2021-11-22
- 期刊:
- 影响因子:8
- 作者:Devonport J;Sully L;Boudalis AK;Hassell-Hart S;Leech MC;Lam K;Abdul-Sada A;Tizzard GJ;Coles SJ;Spencer J;Vargas A;Kostakis GE
- 通讯作者:Kostakis GE
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John Spencer其他文献
Radiological Manifestations of Acute Complications of Treatment
治疗急性并发症的放射学表现
- DOI:
- 发表时间:
2009 - 期刊:
- 影响因子:0
- 作者:
John Spencer;Bobby Bhartia - 通讯作者:
Bobby Bhartia
The effectiveness of alluvial gully remediation in Great Barrier Reef catchments
大堡礁集水区冲积沟壑修复的有效性
- DOI:
10.1016/j.iswcr.2024.07.002 - 发表时间:
2025-03-01 - 期刊:
- 影响因子:7.300
- 作者:
Andrew P. Brooks;John Spencer;Nicholas J.C. Doriean;Robin Thwaites;James Daley;Tim Pietsch;Jorg Hacker;Justin Stout - 通讯作者:
Justin Stout
Saturn's tides control Enceladus' plume
土星的潮汐控制着土卫二的羽流
- DOI:
10.1038/nature12462 - 发表时间:
2013-07-31 - 期刊:
- 影响因子:48.500
- 作者:
John Spencer - 通讯作者:
John Spencer
Inside Enceladus
土卫二内部
- DOI:
10.1038/445376b - 发表时间:
2007-01-24 - 期刊:
- 影响因子:48.500
- 作者:
John Spencer;David Grinspoon - 通讯作者:
David Grinspoon
Crystal Structures of Two Palladacycles from the C–H Activation of 2-(Thiophen-2-yl)pyridine
- DOI:
10.1007/s10870-010-9913-5 - 发表时间:
2010-12-02 - 期刊:
- 影响因子:0.600
- 作者:
Samantha K. Callear;John Spencer;Hiren Patel;John J. Deadman;Michael B. Hursthouse - 通讯作者:
Michael B. Hursthouse
John Spencer的其他文献
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{{ truncateString('John Spencer', 18)}}的其他基金
Workshop: Civic Science: Reframing the Role of Science in Society, October 2-3, 2014 in Washington, DC
研讨会:公民科学:重塑科学在社会中的作用,2014 年 10 月 2-3 日在华盛顿特区
- 批准号:
1352822 - 财政年份:2014
- 资助金额:
$ 54.64万 - 项目类别:
Standard Grant
Dynamic Field Theory Summer School 2010
动态场论暑期学校 2010
- 批准号:
1032119 - 财政年份:2010
- 资助金额:
$ 54.64万 - 项目类别:
Standard Grant
Connectionist and Dynamic Systems Approaches to Development: On the Cusp of a New Grand Theory or Still Too Distributed?
联结主义和动态系统的发展方法:处于新的宏大理论的风口浪尖还是仍然过于分散?
- 批准号:
0446800 - 财政年份:2005
- 资助金额:
$ 54.64万 - 项目类别:
Standard Grant
DHB From Where to What: The Dynamics of Spatial Cognition
DHB 从何处到什么:空间认知的动态
- 批准号:
0527698 - 财政年份:2005
- 资助金额:
$ 54.64万 - 项目类别:
Standard Grant
Divide and Conquer: How Perceived Reference Axes Help Maintain Memory for Locations
分而治之:感知参考轴如何帮助维持位置记忆
- 批准号:
0091757 - 财政年份:2001
- 资助金额:
$ 54.64万 - 项目类别:
Continuing Grant
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Validating protozoa-specific drug targets using peptides from biodiverse gene fragment libraries
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