Advances in covalent drug discovery.
Advances in covalent drug discovery.
复制标题
DOI：
10.1038/s41573-022-00542-z
复制
发表时间：
2022-12
影响因子：
120.1
通讯作者：
Nomura, Daniel K.
中科院分区：
文献类型：
--
作者：
Boike, Lydia;Henning, Nathaniel J.;Nomura, Daniel K.
一个多世纪以来，共价药物一直被用于治疗疾病，但促进共价药物合理设计的工具最近才出现。有目的地在现有配体上添加活性官能团可以实现对靶蛋白的有效和选择性抑制，共价表皮生长因子受体（EGFR）和布鲁顿酪氨酸激酶（BTK）抑制剂用于治疗各种癌症。此外，通过“亲电优先”方法鉴定共价配体也导致了共价药物的发现，例如KRAS（G12C）和SARS-CoV-2主要蛋白酶的共价抑制剂。特别是，KRAS（G12C）抑制剂的发现验证了共价筛选技术的使用，这种技术在过去十年中变得更加强大和广泛。化学蛋白质组学平台已经出现，以补充共价配体筛选和协助配体发现，选择性分析和目标鉴定。本综述展示了共价药物发现的里程碑，重点介绍了从这些项目中吸取的经验教训，以及不断发展的共价药物发现技术工具箱如何促进这一领域的成功。共价药物的合理发现依赖于不断扩大的技术工具集。在这里，Daniel Nomura及其同事强调了在过去十年中取得成功的共价药物，并讨论了促进其发现的工具和策略，描述了两种互补的方法，即配体优先和亲电优先策略。
Covalent drugs have been used to treat diseases for more than a century, but tools that facilitate the rational design of covalent drugs have emerged more recently. The purposeful addition of reactive functional groups to existing ligands can enable potent and selective inhibition of target proteins, as demonstrated by the covalent epidermal growth factor receptor (EGFR) and Bruton’s tyrosine kinase (BTK) inhibitors used to treat various cancers. Moreover, the identification of covalent ligands through ‘electrophile-first’ approaches has also led to the discovery of covalent drugs, such as covalent inhibitors for KRAS(G12C) and SARS-CoV-2 main protease. In particular, the discovery of KRAS(G12C) inhibitors validates the use of covalent screening technologies, which have become more powerful and widespread over the past decade. Chemoproteomics platforms have emerged to complement covalent ligand screening and assist in ligand discovery, selectivity profiling and target identification. This Review showcases covalent drug discovery milestones with emphasis on the lessons learned from these programmes and how an evolving toolbox of covalent drug discovery techniques facilitates success in this field. The rational discovery of covalent drugs depends on an expanding toolset of techniques. Here, Daniel Nomura and colleagues highlight covalent drugs that have achieved success over the past decade and discuss the tools and strategies that facilitate their discovery, describing two complementary approaches, namely, ligand-first and electrophile-first strategies.
登录
查看更多内容
在先前治疗的慢性淋巴细胞性白血病中，阿卡劳替尼与伊布鲁替尼：第一次随机III期试验的结果。
DOI：
10.1200/jco.21.01210
发表时间：
2021-11-01
期刊：
Journal of clinical oncology : official journal of the American Society of Clinical Oncology
影响因子：
--
作者：
Byrd JC;Hillmen P;Ghia P;Kater AP;Chanan-Khan A;Furman RR;O'Brien S;Yenerel MN;Illés A;Kay N;Garcia-Marco JA;Mato A;Pinilla-Ibarz J;Seymour JF;Lepretre S;Stilgenbauer S;Robak T;Rothbaum W;Izumi R;Hamdy A;Patel P;Higgins K;Sohoni S;Jurczak W
通讯作者：
Jurczak W
影响因子：
2.7
作者：
Akama, Tsutomu;Baker, Stephen J.;Plattner, Jacob J.
通讯作者：
Plattner, Jacob J.
影响因子：
8.6
作者：
Boike L;Cioffi AG;Majewski FC;Co J;Henning NJ;Jones MD;Liu G;McKenna JM;Tallarico JA;Schirle M;Nomura DK
通讯作者：
Nomura DK
影响因子：
7.3
作者：
Birkholz, Adam;Kopecky, David J.;Cee, Victor J.
通讯作者：
Cee, Victor J.
影响因子：
56.9
作者：
Anand, K;Ziebuhr, J;Hilgenfeld, R
通讯作者：
Hilgenfeld, R