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TGF Beta INHIBITOR AND PRODRUGS

An inhibitor, prodrug technology, applied in the treatment of diseases in response to TGFβ signaling inhibition, the field of novel TGFβ signaling pathway inhibitors, can solve problems such as toxicity to healthy tissues and cells

Pending Publication Date: 2021-09-03
生物医学研究机构基金会 +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] More generally, many potent drugs are known to provide a number of adverse effects or to be toxic to healthy tissues and cells

Method used

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  • TGF Beta INHIBITOR AND PRODRUGS
  • TGF Beta INHIBITOR AND PRODRUGS
  • TGF Beta INHIBITOR AND PRODRUGS

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0244] Example 1: Synthesis of compounds of formulas I, III and IV:

[0245] Unless otherwise stated, all reactions were performed under an inert atmosphere (N 2 ) under. Anhydrous THF, DCM and ether were obtained from Innovative Technology Inc. Puresolv Solvent Purification System (SPS). Additional anhydrous solvents were purchased and used without any further purification or drying.

[0246] All experiments were monitored by analytical thin layer chromatography (TLC) using silica gel TLC-aluminum plates (Merck 60 F254). Results were visualized under UV light (254 or 365 nm) and displayed using KMnO4 staining if necessary.

[0247] Unless otherwise stated, flash column chromatography was performed on (Teledyne Isco) or on a Puriflash 430 (Interchim). The mobile phase was a gradient of hexane / ethyl acetate or dichloromethane / methanol. In some cases where basic nitrogen was present on the molecule to be purified, the column was preconditioned with 2.5% triethylamine in h...

Embodiment 2

[0318] Example 2: In vitro TGFβ inhibitor activity

[0319] 2.1 Molecular affinity and selectivity determination

[0320] By using KINOMEscan from Eurofins TM techniques to determine the affinity of compounds of formula I for the ALK family, measured as the Kd (dissociation constant). Selectivity to ALK1 (ACVRL1), ALK2 (ACVR1), ALK3 (BMPR1A), ALK4 (ACVR1B), ALK6 (BMPR1B), ACVR2B and TGFβR2 was determined.

[0321] The KINOMEscan screening platform employs an active site-directed competition binding assay to quantitatively measure the interaction between a test compound and a kinase. The KINOMEscan assay does not require ATP and thus reports true thermodynamic interaction affinities.

[0322] The assay is performed by combining three components: DNA-labeled kinase; immobilized ligand; and test compound. The ability of test compounds to compete with immobilized ligands was measured via quantitative PCR of DNA tags.

[0323]Binding reactions were assembled by combining kinas...

Embodiment 3

[0345] Example 3: In vivo studies of TGFβ inhibitors

[0346] Mouse tumor organoids (MTOs) were derived from compound transgenic mice of the C57BL6 / J strain (conditional mutations in Apc, Kras, Trp53, and Tgfbr2, and carrying Lgr5-EGFP / CreER T2 ), and cultured as described in Tauriello et al. 2018 Nature 554(7693):538-543.doi:10.1038 / nature25492. Organoids are tumor epithelial cells grown in a 3D matrix in which they adopt organotypic structures, typically as spheroids with lumens. In this way, cells maintain a relatively normal polarity (meaning that the outer surface, inner / luminal surface, and cell-cell contacts are individually specialized), which is more physiological than conventional 2D cell culture. Furthermore, these organoids are able to recapitulate the complex tumor architecture that recapitulates human cancers, including the recruitment of abundant and tumor-promoting (i.e., TGFβ-rich) stroma; a system for engrafting human-like tumors and studying liver metastase...

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Abstract

A compound of formula (I) with improved TGF Beta signaling pathway inhibitory activity, improved therapeutic efficacy and improved toxicity profile, as well as two prodrugs thereof are disclosed. Compositions comprising said TGF Beta signaling pathway inhibitor and prodrugs thereof are also disclosed. Additionally, present invention discloses said compound of formula (I) and prodrugs thereof for use in a method of treating diseases responsive to TGF Beta signaling pathway inhibition.

Description

technical field [0001] The present invention relates to novel TGFβ signaling pathway inhibitors having improved inhibitory activity, improved therapeutic capacity and improved toxicity profile, and prodrugs thereof (comprising vanillinone-derived fragments or carbamate fragments), which TGFβ signaling inhibitory activity is caged, but a more active TGFβ signaling pathway inhibitor can be delivered in vivo when the prodrug undergoes hydrolysis. Compositions comprising said TGFβ signaling pathway inhibitors and prodrugs thereof are also disclosed. Furthermore, the present invention discloses said TGF[beta] signaling pathway inhibitors and prodrugs thereof for use in methods of treating diseases responsive to inhibition of TGF[beta] signaling. Background technique [0002] Transforming growth factor beta isoforms TGFβ1, TGFβ2 and TGFβ3 are small secreted homodimeric signaling proteins. They are found only in vertebrates and are required for the normal development of various o...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/138A61K31/4709A61P35/00C07D471/00C07C217/18C07D487/04
CPCC07D487/04A61K31/138A61K31/4709A61P35/00C07C217/18A61P35/04A61K45/06
Inventor 达尼埃莱·陶列洛丹尼尔·拜罗姆琼·安东尼·马塔林莫拉莱斯爱德华·巴特列戈麦斯安东尼·列拉埃斯卡尔
Owner 生物医学研究机构基金会
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