E2F activity inhibitory compounds

Details E2F activity inhibitory compounds E2F activity inhibitory compounds

1999-03-30

2004-03-30

Russel, Jeffrey E. (Department: 1654)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

C514S014800, C514S021800, C530S324000, C530S327000, C530S350000

Reexamination Certificate

active

06713449

ABSTRACT:

TECHNICAL FIELD
The present invention relates to a novel peptide useful as a therapeutic agent of diseases such as tumor and arteriosclerosis, for which cellular abnormal growth is responsible, by inhibiting the activity of a transcription factor E2F which regulates the transcription of gene groups involved in the progress of cell cycle to thereby suppress cell growth.
BACKGROUND ART
E2F is a transcription factor of importance for the transcription of a great number of genes involved in the progress of cell cycle and serves as a target protein of tumor suppression gene product Rb [EMBO J., 9, 2179 (1990); Cell, 65, 1053 (1991)]. As proteins comprising E2F, E2F family and DP family have been known. Up to now, five molecules of the E2F family, namely E2F 1 to 5 have been identified, while two molecules of the DP family, namely DP1 and 2, have also been identified. It has been believed that the out of control expression or activity of E2F is deeply involved in the carcinogenesis of a great number of cells [Science, 258, 424 (1992); Trends in Biological Science, 19, 108 (1994)]. It has also been reported that the inhibition of the transcriptional activity of E2F can suppress the growth of smooth muscle cells, which works as the cause of arteriosclerosis [Proc. Natl. Acad. Sci. USA., 92, 5855 (1995)]. Thus, the substance suppressing the E2F activity is useful as a therapeutic agent of tumor or diseases involving the abnormal growth of smooth muscle cells or the like, such as arteriosclerosis. Additionally, the substance may also be effective widely for autoimmune diseases which are exacerbated due to the growth of synovial cell, such as chronic rheumatoid arthritis, or diseases occurring because of the abnormal growth of mesangium cell, such as nephropathy. As to E2F suppressing agents, nucleic acid based compounds have been known, including antisense RNA [Cancer Res., 54, 1402 (1994)] and decoy based on the E2F binding sequence DNA [Proc. Natl. Acad. Sci. USA., 92, 5855 (1995)]. However, no peptides have been known yet as such suppressing agents.
DISCLOSURE OF THE INVENTION
In accordance with the present invention, it is provided a compound represented by the general formula (I);
R
1
—A—R
2
  (I)
(wherein R
1
represents substituted or unsubstituted alkanoyl, substituted or unsubstituted aroyl, substituted or unsubstituted heteroarylcarbonyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted aryloxycarbonyl, substituted or , unsubstituted heteroaryloxycarbonyl or a hydrogen atom; R
2
represents hydroxy, substituted or unsubstituted alkoxy, or substituted or unsubstituted amino; and A represents a peptide sequence comprising a partial amino acid sequence having at least 12 continuous residues in the sequence of the dimerization region or DNA binding region of each E2F family) [simply referred to as “Compound I” hereinafter] or a pharmaceutically acceptable salt thereof. In accordance with the present invention, a pharmaceutical composition comprising the Compound (I) or a pharmaceutically acceptable salt thereof is provided.
In the definition of each group in the formula (I), the alkanoyl includes alkanoyl groups with 1 to 20 carbon atoms, such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyl, lauroyl, and icosanoyl.
The substituted alkanoyl has, the same or different, 1 to 3 substituents such as hydroxy, carboxyl, alicyclic alkyl, substituted or unsubstituted phenyl or fluorenyl.
Herein, the alicylic alkyl includes alicyclic alkyl groups with 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
The substituted phenyl has, the same or different, 1 to 3 substituents such as alkyl, alkoxy, hydroxy, nitro, sulfo, cyano or halogen. The alkyl and the alkyl moiety of the alkoxy include alkyl groups with 1 to 20 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, heptyl, decyl, dodecyl, and icosyl; and the halogen includes each atom of fluorine, chlorine, bromine and iodine.
The aryl moiety of the aroyl and the aryloxycarbonyl includes e.g. phenyl and naphthyl. Each of the substituted aroyl and the substituted aryloxycarbonyl has, the same or different, 1 to 3 substituents such as alkyl, alkoxy, hydroxy, nitro, sulfo, or halogen. The alkyl and the alkyl moiety of the alkoxy and the halogen have the same meanings as defined above, respectively.
The heteroaryl moiety of the heteroarylcarbonyl and the heteroaryloxycarbonyl includes e.g., furyl, thienyl, pyridyl, pyrrolyl, pyrazolyl, pyrimidinyl, pyradinyl, indolyl, quinolyl, isoquinolyl, and quinazolyl. Each of the substituted heteroarylcarbonyl and the substituted heteroaryloxycarbonyl has the same substituents as defined for the substituents of the substituted aroyl.
The alkyl moiety of the alkoxycarbonyl and the alkoxy means the same as defined above. The substituents of the substituted alkoxycarbonyl and the substituted alkoxy include e.g. hydroxy, carboxy, carbamoyl, alicyclic alkyl, substituted or unsubstituted phenyl and fluorenyl. The alicyclic alkyl and the substituent of the substituted phenyl mean the same as defined above, respectively.
The substituted amino has, the same or different, 1 to 2 substituents such as substituted or unsubstituted alkyl, or substituted or unsubstituted aryl. The alkyl and the aryl have individually the same meanings as defined above. The substituents of the substituted alkyl include e.g. hydroxy, carboxy, carbamoyl, alicyclic alkyl and a phenyl group. The alicyclic alkyl has the same meaning as defined above. The substituted aryl has, the same or different, 1 to 3 substituents such as alkyl, alkoxy, hydroxy, nitro, sulfo or halogen. The alkyl and the alkyl moiety of the alkoxy, and the halogen have the same meanings as defined above, respectively.
In accordance with the present invention, the term “E2F” means a protein which binds to the E2F binding sequence in DNA and influences the promoter activity around the sequence. E2F is composed of the E2F family and DP family, and each family has a dimerization region and a DNA binding region. The sequences of the dimerization region and DNA binding region in each family of E2F are described in Cell, 70, 337 (1992); Cell, 70, 351 (1992); Mol. Cell. Biol., 13, 7802 (1993); Mol. Cell. Biol., 13, 7813 (1993); Genes and Dev., 8, 2680 (1994); Genes and Dev., 8, 2665 (1994); Proc. Natl. Acad. Sci. USA., 92, 2403 (1995); Nature, 362, 83 (1993); Mol. Cell. Biol., 15, 2536 (1995) and the like.
The peptide sequence comprising a partial amino acid sequence having at least 12 continuous residues in the sequence of the dimerization region of the E2F includes SEQ ID NO:25, e.g., a sequence represented by the general formula (Ia);
(Ia)

(X
1
)n - (X
2
)n - (X
3
)n - (Ala)n - (X
5
)n -

(X
6
)n - (X
7
)n - (X
8
)n - (X
9
)n - Val -

Gln - Lys - Arg - Arg - Ile -

Tyr - Asp - Ile - Thr - Asn -

Val - (Leu)n - (Glu)n - (Gly)n - (Ile)n -

(X
26
)n - (X
27
)n - (X
28
)n - (X
29
)n -
(wherein “n's in individual amino acid residues are the same or different, and represent 0 or 1; X
1
, X
8
, X
27
and X
28
are the same or different, representing Leu or Ile; X
2
represents Asn or Lys; X
3
represents Trp, Lys, Leu, Ala or Glu; X
5
represents Ala or Ser; X
6
represents Glu, Asp or Asn; X
7
represents Val, Thr or Arg; X
9
represents Lys, Asp, Ala or His; X
26
represents Gln, His, Gly, Asp or Asn; and X
29
represents Ala, Arg, Lys or Glu), and SEQ ID NO: 26, e.g., a sequence represented by the general formula (Ib);
(Ib)

(Y
1
)m - (Y
2
)m - (Y
3
)m - (Gln) - (Y
5
)m -

(Y
6
)m - (Asp)m - (Gln)m - (Y
9
)m - (Asn)m -

Ile - Arg - Arg - Arg - Val -

Tyr - Asp - Ala - Leu - Asn -

Val - Leu - Met - Ala - Y
25
-

(Asn)m - (Y
27
)m - (Ile)m - (Ser)m -
(wherein “m's” in individual amino acid residues are the same or different, and represent 0 or 1; Y
1
represents Asn, Thr, Ala or Tyr; Y
2
represents Glu or Asp; Y
3
represents Ser or

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