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Proteolysis targeting chimera compounds and methods of preparing and using same

一种化合物、结合体的技术，应用在蛋白水解靶向嵌合体化合物及其制备和应用领域，能够解决限制开发、降低蛋白质水平等问题

Inactive Publication Date: 2018-08-03
YALE UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

While genetic techniques such as RNAi, and CRISPR / Cas9 can significantly reduce protein levels, the pharmacokinetic properties (i.e., metabolic stability and tissue distribution) associated with these approaches currently limit their development as clinical agents

Method used

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  • Proteolysis targeting chimera compounds and methods of preparing and using same
  • Proteolysis targeting chimera compounds and methods of preparing and using same
  • Proteolysis targeting chimera compounds and methods of preparing and using same

Examples

Experimental program
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preparation example Construction

[0270] Preparation of compounds of the present invention

[0271] Compounds of formula (I)-(XXXI) can be prepared by the general schemes described herein using synthetic methods known to those skilled in the art. The following examples illustrate non-limiting embodiments of the invention.

[0272] The compounds of the present invention may possess one or more stereocenters, and each stereocenter may independently exist in the (R) or (S) configuration. In certain embodiments, the compounds described herein exist in optically active or racemic forms. It will be understood that the compounds described herein include racemic, optically active, regioisomeric and stereoisomeric forms or combinations thereof that are therapeutically useful as described herein. Preparation of the optically active form is accomplished in any suitable manner including, by way of non-limiting examples, by resolution of the racemic form using recrystallization techniques, synthesis from optically active...

Embodiment

[0352] The present invention will now be described with reference to the following examples. These examples are provided for the purpose of illustration only, and the invention should not be construed in any way as being limited to these examples, but rather should be construed to include any and all variations which are apparent based on the teaching provided herein.

[0353] Methods and Materials

[0354] 1. Biology

[0355] Cell Lines and Materials

[0356] K562 cells were obtained from ATCC and incubated at 37°C, 5% CO 2 Grow in Iscove's Modified Dulbecco's Medium (IMDM) supplemented with 10% FBS, 100 U / mL penicillin and 100 μg / mL streptomycin. HEK293 and SK-BR-3 cells were obtained from ATCC and incubated at 37°C, 5% CO 2 Grow in Dulbecco's modified Eagle's medium (DMEM) supplemented with 10% FBS, 100 U / mL penicillin and 100 μg / mL streptomycin. Phospho-STAT5Y694 (#4322) and phospho-CrkL Y207 (#3181) antibodies were obtained from Cell Signaling Technologies. c-ABL(24...

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Abstract

The present invention includes novel compounds and methods for preventing or treating diseases associated with and / or caused by overexpression and / or uncontrolled activation of a tyrosine kinase in asubject in need thereof. In certain embodiments, the compounds of the present invention comprise a tyrosine kinase inhibitor, a linker and a ubiquitin ligase binder. The methods of the present invention comprise administering to the subject a pharmaceutically effective amount of at least one compound of the invention.

Description

[0001] Cross References to Related Applications [0002] This application claims priority under 35 U.S.C. §119(e) to U.S. Provisional Application No. 62 / 249,501, filed November 2, 2015, which application is hereby incorporated by reference in its entirety. [0003] Statement Regarding Federally Sponsored Research or Development [0004] This invention was made with government support under CA197589 and AI084140 awarded by the National Institutes of Health. The government has certain rights in this invention. Background of the invention [0005] The current inhibitor-based drug paradigm not only restricts drug targeting to those proteins with tractable active sites, but also requires high dosing to achieve ICs sufficient for therapeutic potency. 90 concentration. To circumvent these problems, alternative therapeutic strategies have been used to specifically knock down the target protein. Although genetic techniques such as RNAi, and CRISPR / Cas9 can significantly reduce prot...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/4025C07D207/16C07D417/12
CPCA61K47/55A61K47/555A61P35/00A61P35/02A61P43/00C07D417/14C07K5/06034A61K31/427A61K31/506C07K5/06
Inventor C·克瑞武兹M·图雷E·柯S·詹姆-菲格罗亚
Owner YALE UNIV
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