The Wistar Institute

Other

Bayer Corporation

Bayer Healthcare LLC

Thanos D Halazonetis

Wolfgang Hartwig

Linda B Schultz

Elena S Stavridi

Daniel Scolnick

The present invention provides peptides and peptidomimetics corresponding to part or to the entirety of the region encompassed by residues 360-386 of human p53, said peptides and peptidomimetics characterized by the ability to activate DNA binding of wild-type p53 and of select tumor-derived p53 mutants. Pharmaceutical compositions of the compounds of the invention and methods of using these compositions therapeutically are also provided.

Peptides and peptidomimetics with structural similarity to human p53 that activate p53 function

The present invention relates to methods of identifying modulators of an interaction between 53BP1 and histone H3 (H3). The present invention also relates to methods of use of inhibitors of an interaction between 53BP1 and H3. The present invention further relates to fragments of 53BP1 and H3, as well as other methods and uses.

Methods of identifying an agent that modulates an interaction between 53BP1 and histone H3, and uses thereof

A method for detecting DNA damage in a tissue sample involves contacting an immobilized biological sample with a labeled ligand which binds to human 53Bp1, and examining the immobilized sample for the presence of a label generated-detectable signal concentrated in foci in said sample. The presence of concentrated foci is indicative of DNA damage and the presence of diffuse signal is indicative of a normal sample. Diagnostic reagents contain a ligand that binds to human 53Bp1 associated with a detectable label. Diagnostic kits for detecting DNA damage in a biological sample contain such diagnostic reagents and signal detection components. Compositions that inhibit or antagonize the biological activity of 53Bp1 are identified by suitable assays, and are employed in methods of retarding the growth of a cancer cell.

Methods for detecting DNA damage and screening for cancer therapeutics

The present invention provides peptides and peptidomimetics corresponding to part or to the entirety of the region encompassed by residues 360&#x2013;386 of human p53, said peptides and peptidomimetics characterized by the ability to activate DNA binding of wild-type p53 and of select tumor-derived p53 mutants. Pharmaceutical compositions of the compounds of the invention and methods of using these compositions therapeutically are also provided.

An isolated nucleic acid sequence of a mitotic checkpoint gene, chfr, encodes a Chfr protein having a Forkhead-associated domain and a Ring Finger. This protein is required for regulation of the transition of cells from prophase to metaphase during mitosis. The chfr nucleic acid and Chfr polypeptide are useful in diagnosing tumorigenic cells and in screening for drugs which can inhibit the activity of Chfr in a cancer cell, thereby rendering the cell more sensitive to additional anti-tumor therapies.

Compositions and methods to enhance sensitivity of cancer cells to mitotic stress

The present invention provides peptides and peptidomimetics corresponding to part or to the entirety of the region encompassed by residues 360-386 of human p53, said peptides and peptidomimetics characterized by the ability to activate DNA binding of wild-type p53 and to select tumor-derived p53 mutants. Pharmaceutical compositions of the compounds of the invention and methods of using these compositions therapeutically are also provided.

Modified p53 tetramerization domains which do not hetero-oligomerize with native p53 tetramerization domains are described. These modified p53 tetramerization domains have one or more of the following substitutions in the region of residues 325 to 355 of human p53: Leu330 substituted with Phe; Met340 substituted with Phe; Ala347 substituted with Ile; Leu348 substituted with Met; Ala353 substituted with Leu; Gln354 substituted with Leu; Ala355 substituted with Asp. Also described are p53 proteins containing these modified p53 tetramerization domains linked to a p53 DNA binding domain. These proteins and the nucleic acid sequences encoding them, are useful in ameliorating conditions associated with inappropriate p53 function.

Modified p53 tetramerization domains having hydrophobic amino acid substitutions

Peptides and peptidomimetics with structural similarity to human P53 that activate P53 function

A modified p53 protein or peptide having DNA binding in which amino acid residue 284 of a p53 protein or protein fragment is changed to Arginine or Lysine, is described. Also described are nucleotide sequences encoding the modified protein and vectors capable of expressing it.

Modified p53 constructs which enhance DNA binding

The present invention provides p53 proteins with altered tetramerization domains that retain wild-type p53 function, and the ability to form tetramers and have at least one of the following characteristics: (1) do not hetero-oligomerize with wild-type p53 or tumor-derived p53 mutants, and (2) restricted DNA binding specificity from an alteration in the way that the tetramerization domain orients the DNA binding domains of a p53 tetramer relative to one another. The invention also provides nucleic acids encoding the above proteins and methods of enhancing the cellular response to DNA damaging agents, treating diseases characterized by abnormal cell proliferation, and inducing immune tolerance to facilitate transplants and treatment of autoimmune disease, by administration of proteins of the invention or nucleic acid sequences encoding the proteins of the invention.

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Wynnewood, PA, United States of America

Thanos D Halazonetis