Quantitative Proteomics Reveals Cellular Off-Targets of a DDR1 Inhibitor

Xu, Jiaqian; Zhang, Zhang; Lin, Ligen; Sun, Hongyan; White, Lorenzo V.; Ding, Ke; Li, Zhengqiu

doi:10.1021/acsmedchemlett.9b00658

Cited by 12 publications

(8 citation statements)

References 24 publications

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“…However, these inhibitors are non–selective, which limits further research on the inhibitive effects of specific DDR 12 . Since 2013, the development of new DDR1 inhibitors, such as pyrazolopyrimidine derivatives, monoclonal antibodies, and artificial intelligence (AI)‐generated DDR1 inhibitors, has increased rapidly, which indicates that DDR inhibition may represent a novel therapeutic strategy 13‐15 …”

Section: Introductionmentioning

confidence: 99%

“…12 Since 2013, the development of new DDR1 inhibitors, such as pyrazolopyrimidine derivatives, monoclonal antibodies, and artificial intelligence (AI)generated DDR1 inhibitors, has increased rapidly, which indicates that DDR inhibition may represent a novel therapeutic strategy. [13][14][15] In this article, we review the basic structural characteristics and functions of DDR, the role of DDR in tumorigenesis, and the recent development of DDR inhibitors, aiming to provide new insights into anti-DDR therapy for cancer patients.…”

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confidence: 99%

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Discoidin domain receptors orchestrate cancer progression: A focus on cancer therapies

Gao

Zhou

2021

Cancer Science

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Discoidin domain receptors (DDR), including DDR1 and DDR2, are special types of the transmembrane receptor tyrosine kinase superfamily. DDR are activated by binding to the triple‐helical collagen and, in turn, DDR can activate signal transduction pathways that regulate cell‐collagen interactions involved in multiple physiological and pathological processes such as cell proliferation, migration, apoptosis, and cytokine secretion. Recently, DDR have been found to contribute to various diseases, including cancer. In addition, aberrant expressions of DDR have been reported in various human cancers, which indicates that DDR1 and DDR2 could be new targets for cancer treatment. Considerable effort has been made to design DDR inhibitors and several molecules have shown therapeutic effects in pre–clinical models. In this article, we review the recent literature on the role of DDR in cancer progression, the development status of DDR inhibitors, and the clinical potential of targeting DDR in cancer therapies.

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Section: Introductionmentioning

confidence: 99%

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confidence: 99%

Discoidin domain receptors orchestrate cancer progression: A focus on cancer therapies

Gao

Zhou

2021

Cancer Science

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“…A variety of affinity probes were designed and synthesized by extending the alkyl chain of the parent compound. For example, the probe of kinase inhibitor hypothymycin, C4 propargyl ether, was obtained by lengthening the carbon chain at C4 methyl ether, [38] and discoidin domain receptors 1 (DDR1) inhibitor DR introduced a photo‐crosslinking group at piperazine methyl to afford the probes DR1 and DR2 [39] . From the preliminary structure‐activity relationship (SAR) study, we found the synthetic homologues of isorhamnetin retained the potency, introduction of larger groups may inevitably affect the cellular activity, for some reason such as cellular permeability issue, but fortunately the activity is still acceptable, which indicated the possibility of 3′‐ O substitution elongation on isorhamnetin with retained activity.…”

Section: Resultsmentioning

confidence: 99%

Synthesis of 3′‐O‐Alkyl Homologues and a Biotin Probe of Isorhamnetin and Evaluation of Cytotoxic Efficacy on Cancer Cells

Yang

Zheng

Tursumamat

et al. 2021

Chemistry & Biodiversity

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Isorhamnetin is a natural flavonoid which shows a variety of biological activities such as antioxidant, anti‐inflammatory and antitumor. In order to identify the cellular binding protein of isorhamnetin as potential anti‐cancer target, we first synthesized 3′‐O‐substituted quercetin as isorhamnetin homologues and evaluated the growth inhibitory activity of these derivatives on breast, colon and prostate cancer cell lines. The preliminary results showed that the 3′‐O modification did not affect the cytotoxic activity of the scaffold. Analysis of the co‐crystal structure and the docking pose of isorhamnetin with reported binding protein of isorhamnetin or quercetin indicated the 3′‐O‐substitution groups located outside of the binding pocket, which is in accordance with activity of 3′‐O derivatives. Then a biotin conjugate of isorhamnetin with a tetraethylene glycol (PEG)4 linker at the 3′ position was synthesized and the resulting probe retained the anti‐proliferative activity on cancer cell lines, while the cellular fluorescence analysis showed the distribution of probe inside the cells which indicated the probe had limited cell permeability. Finally, pull down assay both in situ inside cells and in the cell lysates indicated the isorhamnetin biotin probe was capable of protein labeling in cell lysates. These findings provide the isorhamnetin 3′‐O‐biotin probe as a tool to reveal the target proteins of isorhamnetin.

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“…A series of trans-cyclooctene (TCO)-containing probes can be used to monitor the binding interactions of DR inhibitors with their targets within the cell. This proteomics approach revealed that cathepsin D (CTSD) is the main off-target of DR in human cancer cells [ 58 ]. In parallel, OSW-1 is a potent anticancer saponin that has a positive effect on breast cancer cells [ 59 ].…”

Section: Anticancer Activity Of Probesmentioning

confidence: 99%

Chemical Probes and Activity-Based Protein Profiling for Cancer Research

Mazid

Park

Cheekatla

et al. 2022

IJMS

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Chemical probes can be used to understand the complex biological nature of diseases. Due to the diversity of cancer types and dynamic regulatory pathways involved in the disease, there is a need to identify signaling pathways and associated proteins or enzymes that are traceable or detectable in tests for cancer diagnosis and treatment. Currently, fluorogenic chemical probes are widely used to detect cancer-associated proteins and their binding partners. These probes are also applicable in photodynamic therapy to determine drug efficacy and monitor regulating factors. In this review, we discuss the synthesis of chemical probes for different cancer types from 2016 to the present time and their application in monitoring the activity of transferases, hydrolases, deacetylases, oxidoreductases, and immune cells. Moreover, we elaborate on their potential roles in photodynamic therapy.

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Quantitative Proteomics Reveals Cellular Off-Targets of a DDR1 Inhibitor

Cited by 12 publications

References 24 publications

Discoidin domain receptors orchestrate cancer progression: A focus on cancer therapies

Discoidin domain receptors orchestrate cancer progression: A focus on cancer therapies

Synthesis of 3′‐O‐Alkyl Homologues and a Biotin Probe of Isorhamnetin and Evaluation of Cytotoxic Efficacy on Cancer Cells

Chemical Probes and Activity-Based Protein Profiling for Cancer Research

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