Targeting “undruggable” proteins： opportunities and challenges of traditional Chinese herbal medicine

Huimin ZHU; Lei WANG; Mengzhen SHEN; Xisong KE; Yi QU

doi:10.16305/j.1007-1334.2022.2111030

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Targeting “undruggable” proteins： opportunities and challenges of traditional Chinese herbal medicine

更新时间：2022-07-13

- Targeting “undruggable” proteins： opportunities and challenges of traditional Chinese herbal medicine
- Shanghai Journal of Traditional Chinese Medicine Vol. 56, Issue 5, Pages: 14-18(2022)
- 作者机构：
  
  1.上海中医药大学交叉科学研究院（上海 201203）
  2.上海市中药化学生物学前沿基地（上海 201203）
- 作者简介：
- 基金信息：
- DOI：10.16305/j.1007-1334.2022.2111030
  CLC：
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朱慧敏,汪磊,慎梦真等.靶向“不可成药”蛋白：中药的优势和机遇[J].上海中医药杂志,2022,56(05):14-18.

ZHU Huimin,WANG Lei,SHEN Mengzhen,et al.Targeting “undruggable” proteins： opportunities and challenges of traditional Chinese herbal medicine[J].Shanghai Journal of Traditional Chinese Medicine,2022,56(05):14-18.
朱慧敏,汪磊,慎梦真等.靶向“不可成药”蛋白：中药的优势和机遇[J].上海中医药杂志,2022,56(05):14-18. DOI： 10.16305/j.1007-1334.2022.2111030.

ZHU Huimin,WANG Lei,SHEN Mengzhen,et al.Targeting “undruggable” proteins： opportunities and challenges of traditional Chinese herbal medicine[J].Shanghai Journal of Traditional Chinese Medicine,2022,56(05):14-18. DOI： 10.16305/j.1007-1334.2022.2111030.

摘要

靶向治疗是肿瘤治疗领域过去30年来的重要突破之一，但创新药物发现已经出现了挑战，即在世界范围内都出现靶点扎堆或耗尽的现象。另一方面，肿瘤生物学家已经鉴定了多达数百种肿瘤治疗靶标，其中90%以上属于所谓的“无药可靶”或“不可成药”蛋白。针对这种靶点扎堆和“无药可靶”并存的困境，课题组提出“表型发现-靶标鉴定-表型验证”的靶向药物发现新策略，理论上适用于任意目标蛋白。基于这种策略，我国传统中药由于其生物活性好、来源丰富以及有中医临床应用经验等优点，在基于表型的创新药物发现中具有独特的优势，是发现 “无药可靶”或“不可成药”蛋白靶向小分子的重要源泉。与之对应的是，广泛的中药靶标鉴定有望在分子水平阐明中药的作用机制，是中药现代化研究的机遇。

Abstract

Targeted therapy is one of the most important breakthroughs in the field of clinical oncology in the past 30 years， but there have been challenges in the discovery and development of first-in-class drugs in that hundreds of preclinical drugs crowded to a handful of targets or potential therapeutic target was supposed to be exhausted. On the other hand， 90% of more than 500 cancer drivers identified by oncologists are considered as “yet to be drugged” or “undruggable” proteins. In response to the dilemma， we have put forward a new strategy coupling phenotype-based discovery with target identification and phenotype validation， which is potentially applicable to any target protein. Based on this strategy， traditional Chinese herbal medicine （TCHM） has unique advantages in the discovery of first-in-class drugs as it has good biological activity， rich resource and long-term clinical application experience， and TCHM also offers valuable phenotypes that are particularly attractive for phenotype-based discovery of agents targeting “yet to be drugged” or “undruggable” proteins. Correspondingly， large-scale target identification allows us to fully dissect the underlying mechanism-of-action for the clinical phenotypes of TCHM， which also provides an opportunity for the modernization of TCHM.

关键词

中药靶向治疗表型靶标鉴定创新药物发现“不可成药”蛋白

Keywords

traditional Chinese herbal medicinetargeted therapyphenotypetarget identificationfirst-in-class drug discovery“undruggable” protein

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