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Compounds for Nonsense Suppression, Use of These Compounds for the Manufacture of a Medicament for Treating Somatic Mutation-Related Diseases

a technology for somatic mutations and compounds, applied in the field of compound for suppressing nonsense, to achieve the effect of inhibiting the growth of cancer cells

Inactive Publication Date: 2008-10-30
PTC THERAPEUTICS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Mutations of the DNA sequence in which the number of bases is altered are categorized as insertion or deletion mutations (frameshift mutations) and can result in major disruptions of the genome.
These premature stop codons can produce aberrant proteins in cells as a result of premature translation termination.
The inserted amino acid will not necessarily be identical to the original amino acid of the wild-type protein, however, many amino acid substitutions do not have a gross effect on protein structure or function.
One disease for which such a therapeutic strategy may be viable is classical late infantile neuronal ceroid lipofuscinosis (LINCL), a fatal childhood neurodegenerative disease with currently no effective treatment.
However, the use of clitocine as a therapeutic for diseases associated with a nonsense mutation has not been disclosed until now.
Nor has anyone reported the development of an analogue or derivative of clitocine that has utility as a therapeutic for cancer or a disease associated with a nonsense mutation.

Method used

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  • Compounds for Nonsense Suppression, Use of These Compounds for the Manufacture of a Medicament for Treating Somatic Mutation-Related Diseases
  • Compounds for Nonsense Suppression, Use of These Compounds for the Manufacture of a Medicament for Treating Somatic Mutation-Related Diseases
  • Compounds for Nonsense Suppression, Use of These Compounds for the Manufacture of a Medicament for Treating Somatic Mutation-Related Diseases

Examples

Experimental program
Comparison scheme
Effect test

example 1

Preparation of Compounds of the Invention

A. Scheme A:

[0333]3-(6-methyl-benzooxazol-2-yl)-benzoic acid (Compound 3) and similar compounds of the invention may be generally prepared according to Scheme A as follows.

Synthesis of 3-Cyano-benzoic acid methyl ester (I)

[0334]A solution of 3-cyanobenzoic acid (3.15 g, 21.41 mmol) and K2CO3 (4.85 g, 35.48 mmol) in DMF (30 ml) is treated with iodomethane (4.56 g, 32.11 mmol) and stirred at room temperature for 5 h until the complete consumption of the starting material. The reaction mixture is poured into 120 ml of ice-water to precipitate solid. The solid is recrystallized from 100 ml of water-methanol to provide 2.6 g (75.3% yield) of the product as a white crystalline solid; 1H NMR (300 MHz, CDCl3): δ 8.32 (t, 1H), δ 8.26 (td, J1=7.9, J2=1.7, 1H), δ 7.72 (td, J1=7.6, J2=1.7, 1H), δ 7.61 (dt, J1=7.7, J2=7.6, 1H), δ 3.96 (s, 3H); MS+=162.

Synthesis of 3-methoxycarboniumidoyl-benzoic acid methyl ester hydrochloride (II)

[0335]3-Cyano-benzoic ac...

example 2

Nonsense Suppression Activity

[0371]A functional, cell-based translation assay based on luciferase-mediated chemoluminescence (International Application PCT / US2003 / 023185, filed on Jul. 23, 2003, hereby incorporated by reference in its entirety) permits quantitative assessment of the level of nonsense suppression. Human embryonic kidney cells (293 cells) are grown in medium containing fetal bovine serum (FBS). These cells can be stably transfected with the luciferase gene containing a premature termination codon at amino acid position 190. In place of the threonine codon (ACA) normally present in the luciferase gene at this site, each of the 3 possible nonsense codons (TAA, TAG, or TGA) and each of the 4 possible nucleotides (adenine, thymine, cytosine, or guanine) at the contextually important downstream +1 position following the nonsense codon are introduced by site-directed mutagenesis. As such, amino acid 190 in the luciferase gene containing a premature termination codon is TAA,...

example 3

Readthrough Assay

[0374]A functional, cell-based translation assay based on luciferase-mediated chemoluminescence (International Application PCT / US2003 / 023185, filed on Jul. 23, 2003 and incorporated by reference in its entirety) permits assessment of translation-readthough of the normal stop codon in a mRNA. Human embryonic kidney cells (293 cells) are grown in medium containing fetal bovine serum (FBS). These cells are stably transfected with the luciferase gene containing a premature termination codon at amino acid position 190. In place of the threonine codon (ACA) normally present in the luciferase gene at this site, each of the 3 possible nonsense codons (TAA, TAG, or TGA) and each of the 4 possible nucleotides (adenine, thymine, cytosine, or guanine) at the contextually important downstream +1 position following the nonsense codon are introduced by site-directed mutagenesis. As such, amino acid 190 in the luciferase gene containing a premature termination codon is either TAA, ...

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Abstract

The present invention relates to methods, compounds, and compositions for treating or preventing diseases associated with nonsense mutations in an mRNA by administering the compounds or compositions of the present invention. More particularly, the present invention relates to methods, compounds, and compositions for suppressing premature translation termination associated with a nonsense mutation in an mRNA.

Description

RELATED APPLICATIONS[0001]This application claims priority to and the benefit under 35 U.S.C. §119 of U.S. Application Nos. 60 / 617,655, filed Oct. 13, 2004, 60 / 617,634, filed Oct. 13, 2004; 60 / 617,633, filed Oct. 13, 2004, 60 / 617,670, filed Oct. 13, 2004, all of which applications are herein incorporated by reference in their entireties. The present application also claims priority to and the benefit under 35 U.S.C. §119 of U.S. Application Nos. 60 / 617,653, filed Oct. 13, 2004, and 60 / 624,170, filed Nov. 3, 2004. U.S. Application No. 60 / 624,170, filed Nov. 3, 2004, is herein incorporated by reference in its entirety. The present application also incorporates by reference herein in their entireties International Patent Applications entitled “Compounds for Nonsense Suppression, and Methods for Their Use,” filed on Oct. 13, 2005 and identified as Attorney Docket Numbers 19025.040, 19025.041, 19025.042, and 19025.043.FIELD OF THE INVENTION[0002]The present invention relates to methods, ...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/4439C07D413/04A61K31/423C07D263/57C07D413/14A61P35/00C12N5/06
CPCC07D231/12C07D233/64C07D249/08C07D261/08C07D263/32C07F9/65306C07D277/30C07D285/12C07D307/68C07D333/24C07D413/12C07D271/06C07D271/10C07D271/107C07D401/04C07D403/04C07D405/04C07D409/04C07D413/04C07D251/24C07D413/06C07D417/04A61P1/16A61P11/00A61P13/12A61P19/00A61P19/02A61P19/08A61P21/00A61P25/00A61P25/16A61P25/28A61P27/02A61P29/00A61P3/04A61P35/00A61P35/02A61P3/06A61P37/00A61P37/02A61P37/06A61P43/00A61P5/14A61P7/00A61P7/04A61P9/00A61P9/10A61P3/10A61K31/4155A61K31/53
Inventor WILDE, RICHARDWELCH, ELLENKARP, GARY M.
Owner PTC THERAPEUTICS INC
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