Drugging the Undruggable: Targeting the N-Terminal Domain of Nuclear Hormone Receptors.
Drugging the Undruggable: Targeting the N-Terminal Domain of Nuclear Hormone Receptors.
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对不可成药的药物进行药物治疗：针对核激素受体的 N 端结构域。
DOI：
10.1007/978-3-031-11836-4_18
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发表时间：
2022
影响因子：
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通讯作者：
Sadar,MarianneD
中科院分区：
文献类型：
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作者：
Sadar,MarianneD
本章重点介绍靶向核激素受体N-末端结构域的药物的发展，以雄激素受体为例。从历史上看，靶向核激素受体的疗法的发展集中在折叠的C末端配体结合结构域上。传统上不开发针对固有无序的N-末端结构域的疗法，因为它被认为是“不可用药的”。最近的发展表明，有可能将治疗导向N-末端结构域。本章将介绍核激素受体结构域的结构和功能，然后讨论支持N-末端结构域抑制剂开发的基本原理。小分子抑制剂的化学和作用机制将重点描述雄激素受体的N-末端结构域抑制剂，包括临床试验中的抑制剂。
This chapter focuses on the development of drugs targeting the N-terminal domain of nuclear hormone receptors, using progress with the androgen receptor as an example. Historically, development of therapies targeting nuclear hormone receptors has focused on the folded C-terminal ligand-binding domain. Therapies were traditionally not developed to target the intrinsically disordered N-terminal domain as it was considered “undruggable”. Recent developments have now shown it is possible to direct therapies to the N-terminal domain. This chapter will provide an introduction of the structure and function of the domains of nuclear hormone receptors, followed by a discussion of the rationale supporting the development of N-terminal domain inhibitors. Chemistry and mechanisms of action of small molecule inhibitors will be described with emphasis on N-terminal domain inhibitors developed to the androgen receptor including those in clinical trials.