Biomeasure Incorporated

Ipsen Pharma S.a.s.

The Administrators of the Tulane Educational Fund

Other

Societe De Conseils De Recherches Et D'applications Scientifiques Sas

Societe De Conseils De Recherches Et D'applications Scientifiques (s.c.r.a.s.)

The Administration of the Tulane Educational Fund

Sun H Kim

Jacques-Pierre Moreau

Zheng Xin Dong

David H Coy

John E Taylor

Michael DeWitt Culler

Yeelana Shen

Sylviane Moreau

Christophe Thurieau

Arthur E Bogden

Jeanne Mary Comstock

Yeelena Shen

Jundong Zhang

Bonjue Kim

Susan R Keyes

The present invention relates to novel somatostatin-dopamine chimeric analogs and their therapeutic uses for the inhibition, prevention, and/or treatment of neoplasia, neuroendocrine tumors, Cushing's disease/syndrome, and other conditions.

Somatostatin-dopamine chimeric analogs

The invention features targeted cytotoxic compounds and methods relating to their therapeutic use for the treatment of neoplasia and other conditions.

Peptide vectors

Disclosed is a series of somatostatin-dopamine chimeric analogs which retain both somatostatin and dopamine activity in vivo. An example is: 6-n-propyl-8&#x3b2;-ergolinglmethylthioacetyl-D-Phe-c(Cys-Tyr-D-Trp-Lys-Abu-Cys)-Thr-NH.

Peptide-cytotoxic conjugates

Disclosed is a series of somatostatin-dopamine chimeric analogs which retain both somatostatin and dopamine activity in vivo. An example is: 6-n-propyl-8&#x3b2;-ergolinglmethylthioacetyl-D-Phe-c-(Cys-Tyr-D-Trp-Lys-Abu-Cys)-Thr-NH.

Disclosed is a series of somatostatin-dopamine chimeric analogs which retain both somatostatin and dopamine activity in vivo. An example is:

A family of compounds capable of inhibiting the activity of prenyl transferases. The compounds are covered by the four following formulas

Prenyl transferase inhibitors

A linear (i.e., non-cyclic) analog of biologically active amphibian bombesin, mammalian gastrin-releasing peptide (GRP), or mammalian growth hormone releasing factor (GRF), having an active site and a binding site responsible for the binding of the peptide to a receptor on a target cell. Cleavage of a peptide bond in the active site of naturally occurring bombesin, GRP, or GRF is unnecessary for in vivo biological activity. The analog has one of the following modifications: (a) a deletion of an amino acid residue within the active site and a modification of an amino acid residue outside of the active site, (b) a replacement of two amino acid residues within the active site with a synthetic amino acid, a &bgr;-amino acid, or a &ggr;-amino acid residue, or (c) a non-peptide bond instead of a peptide bond between an amino acid residue of the active site and an adjacent amino acid residue.

Octapeptide bombesin analogs

A method of treating liver cancer involving administration to the subject a therapeutically effective amount of a bombesin analog.

Method for treating liver cancer

A linear (i.e., non-cyclic) analog of biologically active amphibian bombesin, mammalian gastrin-releasing peptide (GRP), or mammalian growth hormone releasing factor (GRF), having an active site and a binding site responsible for the binding of the peptide to a receptor on a target cell. Cleavage of a peptide bond in the active site of naturally occurring bombesin, GRP, or GRF is unnecessary for in vivo biological activity. The analog has one of the following modifications: (a) a deletion of an amino acid residue within the active site and a modification of an amino acid residue outside of the active site, (b) a replacement of two amino acid residues within the active site with a synthetic amino acid, a .beta.-amino acid, or a .gamma.-amino acid residue, or (c) a non-peptide bond instead of a peptide bond between an amino acid residue of the active site and an adjacent amino acid residue.

A family of compounds capable of inhibiting the activity of prenyl transferases. The compounds are covered by one of the two following formulas: ##STR1## Each of the R groups is defined in the disclosure.

Inhibitors of prenyl transferases

The invention features linear therapeutic peptides of the following formula: ##STR1## in which A.sup.1 is a D-.alpha.-aromatic amino acid or a D-.alpha.-tethered amino acid; A.sup.2 is Gln, His, 1-methyl-His, or 3-methyl-His; A.sup.3 is the D- or L-isomer selected from Nal, Trp, Phe, and p-X-Phe, where X is F, Cl, Br, NO.sub.2, OH or CH.sub.3 ; A.sup.4 is Ala, Val, Leu, Ile, Nle, or .alpha.-aminobutyric acid; A.sup.5 is Val, Ala, Leu, Ile, Nle, Thr, or .alpha.-aminobutyric acid; A.sup.6 is Gly, Sar, .beta.-Ala, or the D-isomer selected from Ala, N-methyl-Ala, Trp, and Nal; A.sup.7 is His, 1-methyl-His, 3-methyl-His, Lys, or .epsilon.-alkyl-Lys; A.sup.8 is Leu, Ile, Val, Nle, .alpha.-aminobutyric acid, Trp, Pro, Nal, Chx-Ala, Phe, or p-X-Phe, where X is F, Cl, Br, NO.sub.2, OH or CH.sub.3 ; A.sup.9 is Met, Met-oxide, Leu, Ile, Nle, .alpha.-aminobutyric acid, or Cys; each R.sub.1 and R.sub.2, independently, is H, C.sub.1-12 alkyl, C.sub.7-10 phenylalkyl, or COE.sub.1, where E.sub.1 is C.sub.1-20 alkyl, C.sub.3-20 alkenyl, C.sub.3-20 alkynyl, phenyl, 3,4-dihydroxyphenylalkyl, naphthyl, or C.sub.7-10 phenylalkyl; provided that when either R.sub.1 or R.sub.2 is COE.sub.1, the other must be H; and R.sub.3 is OH, NH.sub.2, C.sub.1-12 alkoxy, C.sub.7-10 phenylalkoxy, C.sub.11-20 naphthylalkoxy, C.sub.1-12 alkylamino, C.sub.7-10 phenylalkylamino, C.sub.11-20 naphthylalkylamino; or a pharmaceutically acceptable salt of such peptides.

Growing community of inventors

Chestnut Hill, MA, United States of America

Sun H Kim