Beth Israel Deaconess Medical Center, Inc.

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

Shuo Wei

Kun Ping Lu

Xiao Zhen Zhou

Anton Simeonov

Min Shen

Matthew Brian Boxer

Mindy Irene Emily Davis

Rajan Pragani

Lijun Sun

Michelle Lynn Hall

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 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

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.

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Chestnut Hill, MA, United States of America

Shuo Wei