New techniques and strategies in drug discovery

Du, Jintong; Guo, Jing; Kang, Dongwei; Li, Zhihong; Wang, Guan; Wu, Jianbing; Zhang, Zhen; Fang, Hao; Hou, Xuben; Huang, Zhangjian; Li, Guobo; Lu, Xiaoyun; Liu, Xinyong; Ouyang, Liang; Rao, Li; Zhan, Peng; Zhang, Xiaojin; Zhang, Yihua

doi:10.1016/j.cclet.2020.03.028

Cited by 97 publications

(51 citation statements)

References 183 publications

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“…Hence, we first identified the possible interaction between PARP and BRD4 in breast cancer by using the system biological network. Considering the advantages of dual-target design drug compared with combination drug 45 , 46 , 47 , 48 , 49 , then we rationally designed the first dual-inhibitor of BRD4 and PARP1 by fragment-based combinatorial screening 50 , 51 , 52 . Through chemical synthesis and structure–activity relationship (SAR) study, the candidate compound 19d , also named ADTL-BPI1901, was obtained and showed excellent inhibition activities against both targets and favorable in vivo antitumor efficacy in BRCA1/2 wild-type MDA-MB-468 and MCF-7 xenograft models.…”

Section: Introductionmentioning

confidence: 99%

Design, synthesis, and biological evaluation of quinazolin-4(3H)-one derivatives co-targeting poly(ADP-ribose) polymerase-1 and bromodomain containing protein 4 for breast cancer therapy

Chang

Sun

Shi

et al. 2021

Acta Pharmaceutica Sinica B

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This study was aimed to design the first dual-target small-molecule inhibitor co-targeting poly (ADP-ribose) polymerase-1 (PARP1) and bromodomain containing protein 4 (BRD4), which had important cross relation in the global network of breast cancer, reflecting the synthetic lethal effect. A series of new BRD4 and PARP1 dual-target inhibitors were discovered and synthesized by fragment-based combinatorial screening and activity assays that together led to the chemical optimization. Among these compounds, 19d was selected and exhibited micromole enzymatic potencies against BRD4 and PARP1, respectively. Compound 19d was further shown to efficiently modulate the expression of BRD4 and PARP1. Subsequently, compound 19d was found to induce breast cancer cell apoptosis and stimulate cell cycle arrest at G1 phase. Following pharmacokinetic studies, compound 19d showed its antitumor activity in breast cancer susceptibility gene 1/2 ( BRCA1/2 ) wild-type MDA-MB-468 and MCF-7 xenograft models without apparent toxicity and loss of body weight. These results together demonstrated that a highly potent dual-targeted inhibitor was successfully synthesized and indicated that co-targeting of BRD4 and PARP1 based on the concept of synthetic lethality would be a promising therapeutic strategy for breast cancer.

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Section: Introductionmentioning

confidence: 99%

Design, synthesis, and biological evaluation of quinazolin-4(3H)-one derivatives co-targeting poly(ADP-ribose) polymerase-1 and bromodomain containing protein 4 for breast cancer therapy

Chang

Sun

Shi

et al. 2021

Acta Pharmaceutica Sinica B

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“…At present, more accurate and efficient detection technologies, such as fluorescence in situ hybridization (FISH), next-generation sequencing of tumor tissue (NGS), and sequencing of circulating tumor cells (CTCs), may provide more accurate methods for detecting NTRK fusions and serve as complementary strategies to optimize the current treatments. With the development of computational biology technology, computer-aided drug design has been able to participate in the identification of protein residues in drug development and to gradually clarify the binding characteristics of existing drugs 125 . Additionally, it is beneficial to develop novel TRK drugs and explore drug-resistance mechanisms based upon the sequence, structure and kinetic methods.…”

Section: Concluding Remarks and Future Perspectivesmentioning

confidence: 99%

Development of small-molecule tropomyosin receptor kinase (TRK) inhibitors for NTRK fusion cancers

Jiang

Wang

Liu

et al. 2021

Acta Pharmaceutica Sinica B

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Tropomyosin receptor kinase A, B and C (TRKA, TRKB and TRKC), which are well-known members of the cell surface receptor tyrosine kinase (RTK) family, are encoded by the neurotrophic receptor tyrosine kinase 1, 2 and 3 ( NTRK1, NTRK2 and NTRK3 ) genes, respectively. TRKs can regulate cell proliferation, differentiation and even apoptosis through the RAS/MAPKs, PI3K/AKT and PLC γ pathways. Gene fusions involving NTRK act as oncogenic drivers of a broad diversity of adult and pediatric tumors, and TRKs have become promising antitumor targets. Therefore, achieving a comprehensive understanding of TRKs and relevant TRK inhibitors should be urgently pursued for the further development of novel TRK inhibitors for potential clinical applications. This review focuses on summarizing the biological functions of TRKs and NTRK fusion proteins, the development of small-molecule TRK inhibitors with different chemotypes and their activity and selectivity, and the potential therapeutic applications of these inhibitors for future cancer drug discovery efforts.

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“…It should be noted that the criteria for selecting cases in this review are not comprehensive but typical. All in all, introducing novel strategies and technologies that speed up drug discovery and the drug development cycle is of great importance both in the highly competitive pharmaceutical industry as well as in academia [ 5 , 21 ].…”

Section: Discussionmentioning

confidence: 99%

The increasing impact of Chinese innovative drug research on the global stage with a focus on drug discovery

Luo

Cherukupalli

Hao

et al. 2020

Expert Opinion on Drug Discovery

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New techniques and strategies in drug discovery

Cited by 97 publications

References 183 publications

Design, synthesis, and biological evaluation of quinazolin-4(3H)-one derivatives co-targeting poly(ADP-ribose) polymerase-1 and bromodomain containing protein 4 for breast cancer therapy

Design, synthesis, and biological evaluation of quinazolin-4(3H)-one derivatives co-targeting poly(ADP-ribose) polymerase-1 and bromodomain containing protein 4 for breast cancer therapy

Development of small-molecule tropomyosin receptor kinase (TRK) inhibitors for NTRK fusion cancers

The increasing impact of Chinese innovative drug research on the global stage with a focus on drug discovery

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