CARM1 small-molecule inhibitor and application thereof

A technology of small molecule inhibitors and inhibitors, applied in organic chemistry, drug combination, antineoplastic drugs, etc., can solve the problems of unsatisfactory effect, poor specificity, and low cell activity of cancer cells, and achieve low toxicity of normal cells , inhibition of proliferation, inhibition of tumor cell proliferation

Active Publication Date: 2019-10-25
CHINA AUSTRALIA INST OF TRANSLATIONAL MEDICINE CO LTD NANJING CHINA
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Problems solved by technology

In the past decade, studies have reported some small molecule inhibitors of CARM1, but the low ce

Method used

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  • CARM1 small-molecule inhibitor and application thereof
  • CARM1 small-molecule inhibitor and application thereof
  • CARM1 small-molecule inhibitor and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 11a

[0035] Example 1 1a, 1b preparation method:

[0036] The natural products 1a and 1b are derived from the intestinal bacterium IFB-TL01 of the mantis (Tenodera aridifolia) (preserved in the China Center for Type Culture Collection, preservation number CCTCCM207198). After sonication of bacteria, a bioactive polyketide compound with a new skeleton was isolated by a bioactivity-based fractionation method (Kruzselyi D et al. Journal of Chromatographic Science, 2016, 54(7): 1084-1089.) with high resolution Electrospray ionization mass spectrometry analysis showed that the [M+Na]+ charge-to-mass ratio of the compound was 541.0897. We go further by 1 H and 13 C NMR, 1 H- 1 H COZY analysis to determine its structure ( Figure 1-3 ), single crystal X-ray crystallography analysis shows that the compound is a racemic mixture formed by a pair of enantiomers. Further, we separated the two chiral enantiomers by high performance liquid chromatography ( Figure 4 ), we named them 1a an...

Embodiment 2

[0037] Example 2 Extracellular experiments to detect the effects of 1a and 1b on the catalytic activity of CARM1

[0038] In order to verify whether 1a and 1b can inhibit the methyltransferase activity of CARM1, we first prokaryotically expressed the CARM1 protein with a GST tag and carried out methylation experiments in vitro. Figure 5 As shown, GST-CARM1 protein has methyltransferase activity, which can methylate histone H3. In addition, compared with the control, 1a and 1b can significantly inhibit the activity of CARM1 methyltransferase, and the effect of 1b is better.

[0039] Then we used microthermophoresis (MST) to detect the binding of 1b to CARM1 protein. MST uses the directional motion of particles in a microscopic temperature gradient to determine affinity by measuring changes in microthermophoresis caused by hydration layers (usually caused by changes in biomolecular structure / conformation). Image 6 As shown, in vitro binding experiments show that 1b directly ...

Embodiment 3

[0078] Example 3 Intracellular detection of the effects of 1a and 1b on the catalytic activity of CARM1

[0079] In order to verify the effect of 1a and 1b on the catalytic activity of CARM1 in cells, we used 1a and 1b to treat LNCap cells, collected the cells after 48h, extracted proteins for western blot experiments, and used different histone marker antibodies to detect related histone modifications. Variety, Figure 7 The results showed that 1a and 1b treatment of LNCap cells significantly decreased the modification level of H3R17me2a, but did not affect the modification level of H4R3me2a and H4R3me2s. Figure 8 The results indicated that 1a and 1b did not affect the protein level of CARM1. Therefore, the above experimental results confirmed that 1a and 1b can inhibit the H3R17me2a modification level in LNCap cells, and 1b showed a stronger inhibitory effect.

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Abstract

The invention discloses a CARM1 small-molecule inhibitor and application thereof. The small-molecule inhibitor can effectively inhibit the proliferation of prostate cancer cells. The provided CARM1 small-molecule inhibitor has the low toxicity to normal cells and has the significant inhibitory effect on CARM1-mediated histone H3R17me2a modification and expression of a target gene PSA in the downstream of the histone, the proliferation of tumor cells can be effectively inhibited, and thus the CARM1 small-molecule inhibitor is expected to be developed into a new antitumor drug; and the in vitroand vivo therapeutical effects on prostate cancer, non-small cell lung cancer, breast cancer, acute and chronic leukemia, liver cancer, stomach cancer, colorectal cancer, ovarian cancer, cervical cancer are achieved.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry and relates to a CARM1 inhibitor, in particular to a CARM1 small molecule inhibitor and application thereof. [0002] technical background [0003] According to the 2018 global cancer statistics, there are more than 18 million new cancer cases every year, among which prostate cancer ranks second in the incidence of all male cancers, seriously endangering men's health and life. Early treatment of prostate cancer includes surgical resection, radiotherapy and endocrine therapy, but most patients will eventually relapse and develop castration-resistant prostate cancer. Therefore, the development of new anti-tumor drugs with low toxicity, high efficiency and high specificity has become the key research direction of current scientists. [0004] Coactivator-associated arginine methyltransferase 1 (CARM1), also known as arginine methyltransferase 4 (Protein Arginine Methyltransferase 4, PRMT4), is an im...

Claims

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Application Information

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IPC IPC(8): C07C62/38A61P35/00A61P35/02
CPCC07C62/38A61P35/00A61P35/02C07C2603/94
Inventor 赵权鞠君毅
Owner CHINA AUSTRALIA INST OF TRANSLATIONAL MEDICINE CO LTD NANJING CHINA
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