CETSA and thermal proteome profiling strategies for target identification and drug discovery of natural products

Tu, Yanbei; Tan, Lihua; Tao, Hongxun; Li, Yanfang; Liu, Hanqing

doi:10.1016/j.phymed.2023.154862

Cited by 24 publications

(7 citation statements)

References 121 publications

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“…1 B), with an IC 50 of 4.28 µM. Binding of chemicals to the target protein appears to improve the thermal stability and relative protease resistance [ 14 , 15 ]. CETSA (cellular thermal shift assay, CETSA) is widely used to verify the thermal stabilization improvement under heating conditions on binding of small molecules to target proteins [ 16 ].…”

Section: Resultsmentioning

confidence: 99%

β-carboline derivative Z86 attenuates colorectal cancer cell proliferation and migration by directly targeting PI3K

Nie,

Chang,

Huang

et al. 2024

Nat. Prod. Bioprospect.

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Phosphoinositide 3-kinase (PI3Ks) are lipid kinases widely involved in cell proliferation, metastasis and differentiation. Constitutive activation of the PI3K/Akt/mTOR signaling are well confirmed in colorectal cancers (CRCs). In this study, we identified isopropyl 9-ethyl-1-(naphthalen-1-yl)-9 H-pyrido[3,4-b] indole-3-carboxylate (Z86), as a novel PI3Kα inhibitor with the IC50 value of 4.28 µM. The binding of Z86 to PI3Kα was further confirmed with DARTS and CETSA assay. Immunofluorescence analysis and western blotting data demonstrated that Z86 effectively attenuated PI3K/AKT pathway. Z86 caused dramatic proliferation inhibition of CRCs through G0/G1 cycle arrest rather than apoptosis induction. Besides, the migration of CRCs was also relieved by Z86. The present study not only identified Z86 as a novel PI3Kα inhibitor with potent inhibitory efficiency on PI3K-mediated CRCs growth and migration, but also elucidated a reasonable molecular mechanism of Z86 in the Wnt signaling pathway inhibition. Graphical Abstract

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Section: Resultsmentioning

confidence: 99%

β-carboline derivative Z86 attenuates colorectal cancer cell proliferation and migration by directly targeting PI3K

Nie,

Chang,

Huang

et al. 2024

Nat. Prod. Bioprospect.

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“…Each group was heated for 3 min. After heating all samples, the samples were repeatedly freeze–thaw-cracked . This was followed with western blot analysis.…”

Section: Methodsmentioning

confidence: 99%

Santacruzamate A Alleviates Pain and Pain-Related Adverse Emotions through the Inhibition of Microglial Activation in the Anterior Cingulate Cortex

Qin,

Liu,

Wang

et al. 2024

ACS Pharmacol. Transl. Sci.

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Chronic pain is a complex disease. It seriously affects patients' quality of life and imposes a significant economic burden on society. Santacruzamate A (SCA) is a natural product isolated from marine cyanobacteria in Panama. In this study, we first demonstrated that SCA could alleviate chronic inflammatory pain, pain-related anxiety, and depression emotions induced by complete Freund's adjuvant in mice while inhibiting microglial activation in the anterior cingulate cortex. Moreover, SCA treatment attenuated lipopolysaccharide (LPS)-induced inflammatory response by downregulating interleukin 1β and 6 (IL-1β and IL-6) and tumor necrosis factor-α (TNF-α) levels in BV2 cells. Furthermore, we found that SCA could bind to soluble epoxide hydrolase (sEH) through molecular docking technology, and the thermal stability of sEH was enhanced after binding of SCA to the sEH protein. Meanwhile, we identified that SCA could reduce the sEH enzyme activity and inhibit sEH protein overexpression in the LPS stimulation model. The results indicated that SCA could alleviate the development of inflammation by inhibiting the enzyme activity and expression of sEH to further reduce chronic inflammatory pain. Our study suggested that SCA could be a potential drug for treating chronic inflammatory pain.

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“…The CETSA procedure was performed as previously reported [ 30 ]. The NIH/3T3 cells were collected and cultured with ATG at a dose of 100 µM or DMSO for 1 h, washed three times with PBS, and collected in 15 mL centrifuge tubes.…”

Section: Methodsmentioning

confidence: 99%

Arctigenin from Fructus arctii Exhibits Antiaging Effects via Autophagy Induction, Antioxidative Stress, and Increase in Telomerase Activity in Yeast

Chen,

Li,

et al. 2024

Antioxidants

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Aging is often accompanied by irreversible decline in body function, which causes a large number of age-related diseases and brings a huge economic burden to society and families. Many traditional Chinese medicines have been known to extend lifespan, but it has still been a challenge to isolate a single active molecule from them and verify the mechanism of anti-aging action. Drugs that inhibit senescence-associated secretory phenotypes (SASPs) are called “senomorphics”. In this study, arctigenin (ATG), a senomorphic, was screened from the Chinese medicine Fructus arctii using K6001 yeast replicative lifespan. Autophagy, oxidative stress, and telomerase activity are key mechanisms related to aging. We found that ATG may act through multiple mechanisms to become an effective anti-aging molecule. In exploring the effect of ATG on autophagy, it was clearly observed that ATG significantly enhanced autophagy in yeast. We further verified that ATG can enhance autophagy by targeting protein phosphatase 2A (PP2A), leading to an increased lifespan. Meanwhile, we evaluated the antioxidant capacity of ATG and found that ATG increased the activities of the antioxidant enzymes, thereby reducing reactive oxygen species (ROS) and malondialdehyde (MDA) levels to improve the survival of yeast under oxidative stress. In addition, ATG was able to increase telomerase activity by enhancing the expression of EST1, EST2, and EST3 genes in yeast. In conclusion, ATG exerts anti-aging effects through induction of autophagy, antioxidative stress, and enhancement of telomerase activity in yeast, which is recognized as a potential molecule with promising anti-aging effects, deserving in-depth research in the future.

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CETSA and thermal proteome profiling strategies for target identification and drug discovery of natural products

Cited by 24 publications

References 121 publications

β-carboline derivative Z86 attenuates colorectal cancer cell proliferation and migration by directly targeting PI3K

β-carboline derivative Z86 attenuates colorectal cancer cell proliferation and migration by directly targeting PI3K

Santacruzamate A Alleviates Pain and Pain-Related Adverse Emotions through the Inhibition of Microglial Activation in the Anterior Cingulate Cortex

Arctigenin from Fructus arctii Exhibits Antiaging Effects via Autophagy Induction, Antioxidative Stress, and Increase in Telomerase Activity in Yeast

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