University of Florida Research Foundation, Incorporated

University of South Florida

The United States Government As Represented by the Department of Veterans Affairs

H. Lee Moffitt Cancer Center and Research Institute, Inc.

Other

University of Colorado

Texas Tech University System

David A Ostrov

Mildred Enid Acevedo-Duncan

Satya Narayan

Aruna S Jaiswal

Thomas Cardon Rowe

William G Cance

Daniel M Sullivan

Vita Golubovskaya

Wishrawana Sarathi Ratnayake

Joel G Turner

Diondra Denise Hill

Arun Srivastava

Ann Progulske-Fox

Sukwon Hong

Aaron Michels

Peter W Stacpoole

Peter A Gottlieb

Brian Keith Law

Chen Liu

Thomas J Anchordoquy

George S Eisenbarth

Hla Yee Win

Elena V Kurenova

Paul Trippier

Prajit P Pillai

Srinidhi Jayaraman

Tom Abbruscato

Vardan T Karamyan

Anisul Islam

Maki Nakayama

Christopher Apostolatos

Shraddha R Desai

Carmen J Allegra

Debra E Akin

William A Dunn

Patrick Corsino

Minjel Shah

Hercules Apostolatos

The present invention includes a composition and method of allosterically potentiating the activity of neurolysin comprising contacting the neurolysin with an amount of a histidine-containing dipeptide that is an allosteric that increases the activity of neurolysin.

Enhancers of neurolysin activity

The subject invention pertains to methods of treating colorectal cancer by administering an atypical PKC inhibitor. The inhibitors of aPKC useful in the methods of the instant invention include ACPD, ICA-1, DNDA and &#x3b6;-Stat. Also provided are methods of measuring the susceptibility of colon cancer cells of a subject to inhibitors of aPKCs.

Method of treating colorectal cancers using a PKC inhibitor

The invention pertains to a method of treating melanoma by administering to a subject in need thereof, a composition comprising a therapeutically effective amount of an inhibitor of PKC-&#x3b6; and/or PKC-&#x3b9;. Non-limiting examples of an inhibitor of PKC-&#x3b6; and/or PKC-&#x3b9; include ICA-1 and ACPD. The invention also provides PKC-&#x3b6; and/or PKC-&#x3b9; as biomarkers for identifying a melanoma in a subject as likely to be responsive or non-responsive to a therapy using an inhibitor of PKC-&#x3b6; and/or PKC-&#x3b9;. Accordingly, a method of identifying a subject having a melanoma as being responsive or non-responsive to a melanoma therapy with an inhibitor of PKC-&#x3b6; and/or PKC-&#x3b9; based on the levels and/or activity of PKC-&#x3b6; and/or PKC-&#x3b9; mRNA or protein in the melanoma cells from the subject are also provided.

Method of treating melanoma using an inhibitor of an atypical protein kinase C

The invention provides methods of preventing, treating or ameliorating autoimmune diseases, such as diabetes and celiac disease, by decreasing the binding of MHC class II molecules to antigenic peptides or fragments of antigenic peptides of the autoimmune disease by the administration of small organic compounds. The invention also provides pharmaceutical compositions comprising the therapeutically effective small organic compounds and methods of using the same.

Compounds that modulate autoimmunity and methods of using the same

Topoisomerase II alpha (topo II&#x3b1;) is exported from the cell nucleus in human myeloma cells by a chromosome-maintenance protein-1 (CRM1)-dependent mechanism, resulting in topo II inhibitor resistance. The nuclear export signal (NES) of topo II&#x3b1; is unique, making it a potential target for small molecule inhibitors. Small molecules NES inhibitors were identified, which inhibited binding of topo II&#x3b1; to the export receptor CRM1. Inhibition was specific to topo II&#x3b1; as p53 trafficking was unaffected along with topo II&#x3b1; protein expression and function (decatenation). These topo II&#x3b1;-specific nuclear export inhibitors may potentially lead to a new approach in circumventing drug resistance in multiple myeloma. The compounds provide a protocol for treating multiple myeloma or an oncogenic disease. Further, the topoisomerase II nuclear export signal inhibitor may be combined with a topoisomerase II inhibitor.

Drug targets to overcome de novo drug-resistance in multiple myeloma

The invention features compositions and methods that are useful for the treatment of neoplasia (e.g., pancreatic cancer, colon cancer, brain cancer) by increasing DNA damage, reducing nucleotide synthesis, and reducing base excision repair (BER).

Therapeutic combinations for use in neoplasia

The subject invention pertains to uses of PKC-iota inhibitors for treatment of breast cancer. In one embodiment, the subject invention provides novel uses of 1H-imidazole-4-carboxamide, 5-amino-1-[2,3-dihydroxy-4-[(phosphonooxy)methyl]cyclopentyl]-,[1R-(1&#x3b1;, 2&#x3b2;, 3&#x3b2;, 4&#x3b1;)] (ICA-1) and related compounds for treatment of breast cancer. The compounds of the subject invention have potent anti-proliferative effects against human breast cancer cells. The compounds of the subject invention also inhibit the phosphorylation of IKK-&#x3b1;/IKK-&#x3b2;, induce chromatin condensation, and/or induce DNA fragmentation in cancer cells.

Use of PKC-iota inhibitors for the treatment of breast cancer

A method of treating ovarian cancer by administering a PKC inhibitor is presented herein. It was found that administering a PKC inhibitor, such as ACPD or ICA-1, to ovarian cancer cells inhibited cancer cell proliferation.

Method of treating ovarian cancer using a PKC inhibitor

The invention features compositions and methods that are useful for the treatment of neoplasia by reducing base excision repair (BER). Such compositions are useful, for example, for enhancing the efficacy of known chemotherapeutics, such as DNA alkylating agents. In particular, the invention features agents that mimic the interaction of APC with pol-&#x3b2;. Such agents reduce the activity of long patch- and single nucleotide-base extension repair pathways.

Compositions and methods of treating neoplasia

The invention features compositions and methods that are useful for the treatment of neoplasia (e.g., breast cancer) by increasing DNA damage and reducing base excision repair (BER).

A method of treating cancer in a subject comprising the step of administering to the subject in need thereof an effective amount of a combination of a compound that binds a nuclear export signal (NES inhibitor) on topoisomerase II&#x3b1; and a topoisomerase inhibitor. Twenty small molecule inhibitors (SMI) that bind to the two nuclear export sequences (NES) topo II&#x3b1; have been identified from the NCI database using computer-generated molecular modeling. These SMI will improve the effectiveness of topo II directed therapeutics, particularly in the treatment of diseases such as multiple myeloma (MM). In vitro apoptosis assays indicate that these drugs may be effective as single agents or in combination with currently used cancer drugs that target topo II.

Nuclear export inhibitors of topoisomerase II alpha

The invention relates to cyclin dependent kinase inhibitor compounds and methods of identifying and using them. The invention further relates to pharmaceutical compositions for treating cell proliferative disorders, especially cancer.

Cyclin dependent kinase inhibitors

The subject application provides small compounds that are able to suppress autophagy in various cells. These compounds are useful in augmenting the existing treatments of various cancers and microbial/parasitic infections. Thus, the subject application also provides methods of treating various types of cancers and microbial/parasitic infections. Also provided by the subject application are methods of suppressing the expansion of autophagosomes within cells or individuals and inhibiting the lipidation of autophagy-related protein 8 (Atg8).

Methods and compositions for the treatment of cancers and pathogenic infections

The present invention relates to compounds as novel thymidylate synthase inhibitors, novel strategies to treat or prevent neoplasia in a subject, methods and compositions thereof.

Methods and compositions for treating neoplasia

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Gainesville, FL, United States of America

David A Ostrov