Beth Israel Deaconess Medical Center, Inc.

National Institutes of Health, a Component of the US Dept. of Health & Human Services

Xiao Zhen Zhou

Kun Ping Lu

Shuo Wei

Anton Simeonov

Min Shen

Matthew Brian Boxer

Mindy Irene Emily Davis

Rajan Pragani

Lijun Sun

Michelle Lynn Hall

Gerburg Wulf

Anton Momtchilov Simeonov

The invention features compositions and methods for inhibiting the Pin1 protein, and the treatment of disorders characterized by elevated Pin1 levels.

Methods and compositions for the inhibition of PIN1

The present invention relates to the treatment of Pin1-associated disorders (e.g., disorders characterized by elevated Pin1 activity) with arsenic trioxide, optionally in combination with a retinoic acid compound. Pin1-associated disorders may include, for example, proliferative disorders (e.g., cancers), inflammatory conditions, and autoimmune disorders associated with aberrant levels of Pin1 activity.

Arsenic trioxide for treatment of PIN1-associated disorders

The invention features all-trans retinoic acid (ATRA)-related compounds capable of associating with Pin1 and methods of treating a proliferative disorder characterized by elevated Pin1 marker levels, Pin1 degradation, and/or reduced Pin1 Ser71 phosphorylation in a subject by administering an ATRA-related compound. The invention also features methods of treating proliferative disorders, autoimmune diseases, and addiction conditions (e.g., diseases, disorders, and conditions characterized by elevated Pin1 marker levels) by administering an ATRA-related compound in combination with another therapeutic compound.

Enhanced ATRA-related compounds for the treatment of proliferative diseases, autoimmune diseases, and addiction conditions

The invention features methods of treating a proliferative disorder characterized by elevated Pin1 marker levels and/or reduced Pin1 Ser71 phosphorylation in a subject by administering a retinoic acid compound. Additionally, the invention features methods of treating proliferative disorders (e.g., proliferative disorders characterized by elevated Pin1 marker levels) by administering a retinoic acid compound in combination with another anti-proliferative compound. Finally, the invention also features methods including high-throughput screens for discovering and validating Pin1 inhibitors.

Methods and compositions for the treatment of proliferative disorders

The present invention features methods and compositions for the generation of conformation-specific antibodies.

Methods for administering peptides for the generation of effective c/s conformation-specific antibodies to a human subject in need thereof

Methods and compositions for the inhibition of Pin1

Biomarkers and driver mutations for diagnosis and prognosis of Pin 1-associated diseases are disclosed. In one embodiment, the methods for diagnosis of Pin 1-associated diseases may include detecting the level of Pin1 to stage abnormal cell growth, such as breast or prostate cancer. In another embodiment, the methods include evaluating the efficacy of a treatment of abnormal cell growth, such as cancer, by monitoring the levels of Pin1. In another embodiment, the methods include using driver mutations to determine the pharmacogenetics of abnormal cell growth, such as cancer. In the present disclosure, elevated active monomeric Pin1 levels may be detected by Pin1 biomarkers, which may include Pin1 Q33K or E100D driver mutations, Pin1 protein or transcript overexpression, dephosphorylation of Pin1 on Ser71, dephosphorylation of S16, phosphorylation of S65, phosphorylation of S138, deacetylation of Pin1 on K13 and deacetylation of K46, and/or desumoylation of Pin1 on K6 and desumolation of K63, among others.

Biomarkers for Pin1-associated disorders

The present disclosure describes how all-retinoic acid (ATRA) binds and inhibits Pin1 activity and induces degradation of the activated Pin1 monomer selectively in cancer cells. Identification of the binding mechanism of ATRA with Pin1 confirm ATRA binding specificity to Pin1 residues in the PPIase active site, thus demonstrating that drug-induced Pin1 ablation has potent anticancer activity, such as in acute promyelocytic leukemia (APL), by inducing PML-RARa degradation, as well as against other types of cancer and diseases that are associated with Pin1 overexpression, such as aggressive triple negative breast cancer, lupus, asthma, cocaine addiction, among others, due to their unique ability to simultaneously block numerous cancer-driving pathways, with relatively lower toxicity. The present disclosure also provides a rationale for developing sustained released ATRA-containing formulations. ATRA-containing formulations may be used in combinations with other existing therapies including chemotherapy or molecularly targeted drugs and other standard of care.

ATRA for modulating Pin1 activity and stability

The present invention features methods and compositions for the generation and use of conformation-specific antibodies or fragments thereof.

Methods and compositions for the generation and use of conformation-specific antibodies

The present invention features methods and compositions for the generation and use of conformation-specific anti-bodies or fragments thereof.

Methods for the use of Pin1 as a marker of abnormal cell growth are disclosed. In one embodiment, the method includes detecting a level of Pin1 to stage an abnormal cell growth, such as breast or prostate cancer. In another embodiment, the method includes evaluating the efficacy of a treatment of an abnormal cell growth, such as cancer, by monitoring the levels of Pin1. In another embodiment, the method includes evaluating the extent of metastasis of abnormal cell growth, such as cancer. The levels of Pin1 can be protein levels or nucleic acid levels.

Pin1 as a marker for abnormal cell growth

The invention relates to methods and compositions of WW-domains as phosphoserine and phosphothreonine binding modules. The WW-domain containing polypeptides of the invention can be used, for example, to regulate cell growth; to treat neurodegenerative diseases; to screen for substances that modulated interactions between WW-domain containing polypeptides and phosphorylated ligands; as drug targeting vehicles; to direct protein degradation; and in the treatment of certain diseases or conditions characterized by aberrant WW-domain containing polypeptides or their ligands.

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Newton, MA, United States of America

Xiao Zhen Zhou