Selective apoptotic induction in cancer cells including activation of procaspase-3

A kind of caspase enzyme, caspases technology, applied in the direction of organic chemistry and so on

Inactive Publication Date: 2008-05-21
THE BOARD OF TRUSTEES OF THE UNIV OF ILLINOIS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, because these compounds target upstream (or mid-upstream) positions on the apoptotic cascade, cancers with mutations in proteins downstream of these members may remain resistant to the possible beneficial effects of these compounds

Method used

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  • Selective apoptotic induction in cancer cells including activation of procaspase-3
  • Selective apoptotic induction in cancer cells including activation of procaspase-3
  • Selective apoptotic induction in cancer cells including activation of procaspase-3

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0102] Example 1. Caspase zymogen activating compounds

[0103] Mutations or aberrant expression of proteins involved in the apoptotic cascade are common hallmarks of cancer. These changes prevent the transmission of pro-apoptotic signals to the executor caspases, thereby preventing apoptosis-induced cell death and allowing cell proliferation. Caspase-3 and caspase-7 are key executor caspases that exist as inactive zymogens activated by upstream signals. Importantly, procaspase-3 expression levels were significantly higher in certain cancer cells than in noncancerous control cells. We report here the identification of small molecules that directly activate the pro-caspase-3 zymogen to active caspase-3. The specific compound PAC-1 acts to activate in vitro, EC 50 is approximately 220 nmol, and this compound induces apoptosis in a variety of cancer cell lines.

[0104] Unlike many known anticancer drugs, cells treated with PAC-1 exhibited immediate activation of procaspase-3...

Embodiment 2

[0139] Example 2. Synthesis of pro-caspase activating compounds.

[0140] PAC-1 and other compounds were prepared according to the following schemes such as Scheme 1 and / or Scheme 2. Other variants can be prepared according to methods known in the art.

[0141]

[0142] plan 1

[0143] In a specific example, PAC-1 was prepared according to Scheme 2:

[0144]

Embodiment 3

[0145] Example 3. Analogs of PAC-1.

[0146] Analogous compounds of PAC-1 were prepared and evaluated for their ability to directly activate purified procaspase-3 zymogen in vitro.

[0147] Table 2. Activity of PAC-1 and similar compounds.

[0148]

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Abstract

Compounds and related methods for synthesis, and the use of compounds in therapy for the treatment of cancer and selective induction of apoptosis in cells are disclosed. Compounds are disclosed in connection with modification of procaspases such as procaspase-3, and particular embodiments are capable of direct activation of procaspase-3 and procaspase-7 to the effector forms of caspase-3 and caspase-7. Procaspase-3 levels can vary among cancer cell types; several types have relatively high levels and can have increased susceptibility to chemotherapy by compounds and methods herein. Therapeutic applications are relevant for a variety of cancer conditions and cell types, e.g. breast, lung, brain, colon, renal, adrenal, melanoma, and others.

Description

[0001] Cross References to Related Applications [0002] Pursuant to 35USC119(e), this application claims priority based on U.S. Provisional Application Serial No. 60 / 684,807 filed May 26, 2005 and U.S. Provisional Application Serial No. 60743878 filed March 28, 2006, Both provisional applications are incorporated by reference into this application in their entirety. [0003] Statement Regarding Federally Sponsored Research or Development [0004] This invention was made with government support under NSF Grant / Contract CHE-0134779 awarded by the National Science Foundation. The government has certain rights in this invention. Background technique [0005] Apoptosis or programmed cell death plays an extremely important role in the development and homeostasis of all multicellular organisms (Shi Y, 2002, Molecular Cell 9:459-470). A common hallmark of cancer is its resistance to natural apoptotic signals. This resistance is often due to up- or down-regulation of key proteins ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/497C07D241/04
Inventor P·J·赫甘罗斯尔K·S·帕特G·W·陈J·M·皮尔森
Owner THE BOARD OF TRUSTEES OF THE UNIV OF ILLINOIS
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