Compounds that selectively and effectively inhibit hakai-mediated ubiquitination, as Anti-cancer drugs

A compound, selected technology, applied in the direction of drug combination, active ingredients of heterocyclic compounds, medical preparations containing active ingredients, etc., can solve problems that have not yet been disclosed

Pending Publication Date: 2021-11-19
FUNDACION PROFESOR NOVOA SANTOS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, until now, no compounds capable of effectively inhibiting Hakai-mediated ubiquitination have been disclosed that are particularly suitable as therapeutic tools for the treatment of cancer.

Method used

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  • Compounds that selectively and effectively inhibit hakai-mediated ubiquitination, as Anti-cancer drugs
  • Compounds that selectively and effectively inhibit hakai-mediated ubiquitination, as Anti-cancer drugs
  • Compounds that selectively and effectively inhibit hakai-mediated ubiquitination, as Anti-cancer drugs

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0302] Example 1. Synthesis

[0303] Compounds listed throughout this specification can be prepared according to the following general synthetic routes:

[0304]

Embodiment 2

[0306] 2.1. Materials and methods

[0307] Protein and ligand models. The X-ray crystal structure of the phosphotyrosine-binding domain of Hakai (PDB 3VK6) was downloaded from the Protein Data Bank and the dimer was modeled using appropriate symmetry operations. Amino acid protonation was performed at a pH of 7.2 using the pdb2pqr server. 3D models of the ligands were constructed using the Virtual Screening and Data Management Integrated Platform (VSDMIP), as described elsewhere. Briefly, the initial 3D coordinates of each ligand were generated with CORINA [Sadowski, J.; Gasteiger, J.; Klebe, G. Comparison of Automatic Three-Dimensional Model Builders Using 639X-Ray Structures. J. Chem. Inf. Comput. Sci. 1994, 34, 1000-1008 (DOI: 10.1021 / ci00020a039)]. Afterwards, a wide variety of conformers were generated using ALFA [4], and atomic partial charges calculated by MOPAC were assigned to each conformer by employing the AM1 semi-empirical model and the ESP method. All ligand ...

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Abstract

The present invention provides a class of compounds, which includes enantiomers and pharmaceutically acceptable salts thereof, that selectively and effectively inhibit Hakai-mediated ubiquitination, preferably without affecting Hakai protein levels, thereby representing excellent anti-cancer drugs useful in the treatment of a variety of cancers, such as carcinomas, in particular, tumors arising from the epithelial layers of the gastrointestinal track including month (oral cancer), esophagus, stomach, and small and large intestines (such as rectal or colon cancer). It also includes skin cancer, mammary gland (breast cancer), pancreas cancer, lung cancer, head and neck cancer, liver cancer, ovary cancer, cervix cancer, uterus cancer, gallbladder cancer, penile cancer, and urinary bladder cancer (such as renal, prostate or bladder cancer).

Description

technical field [0001] The present invention relates to a new class of compounds and compositions comprising the compounds. The compounds and compositions (eg, pharmaceutical compositions) of the invention are useful as agents for the treatment of cancer. Background technique [0002] Carcinoma, the most common type of cancer, arises from epithelial cells. The transition from adenoma to carcinoma is associated with loss of E-cadherin and, as a result, disruption of cell-cell contacts. E-cadherin is a tumor suppressor that is downregulated during Epithelial-to-mesenchymal transition (EMT); indeed, its loss is a predictor of poor prognosis. Hakai is an E3 ubiquitin ligase protein that mediates E-cadherin ubiquitination, endocytosis, and eventual degradation, resulting in altered cell-cell contacts. Although E-cadherin is the most established substrate for Hakai activity, other regulated molecular targets of Hakai may be involved in cancer cell plasticity during tumor progre...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/41A61K31/4439A61K31/454A61K31/497A61K31/501A61K31/5355A61K31/55A61P35/00
CPCA61K31/41A61K31/4439A61K31/454A61K31/497A61K31/501A61K31/5355A61K31/55A61P35/00A61K31/427A61K31/433A61K31/4709A61K31/496A61K31/5377
Inventor 安吉莉卡·菲格罗亚·康德-瓦尔维斯费德里科·加戈·巴德纳斯奥莱亚·安蒂亚·马蒂尼斯·伊格莱西亚斯拉奎尔·卡巴洛·卡斯托萨阿尔瓦罗·科特斯·卡布雷拉阿尔巴·卡萨斯·派斯
Owner FUNDACION PROFESOR NOVOA SANTOS
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