Yale University

University of South Florida

University of Pittsburgh

New York University

University of Central Florida Research Foundation Inc

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

Andrew D Hamilton

Said M Sebti

Richard Jove

James Turkson

Kenneth Jay Barr

Wang Shen

Saul H Rosenberg

Stephen J O'Connor

Stephen A Fakhoury

Le Wang

Gerard M Sullivan

David John Augeri

Jin Q Cheng

Katherine J Kayser-Bricker

Kenneth J Henry

James T Wasicak

Sunil Kumar

Andrew Stewart Tasker

Bryan K Sorensen

Justin T Ernst

Douglas M Kalvin

Rolf E Swenson

Indrani W Gunawardana

David A Janowick

Lissa T J Nelson

Rishi Kumar Jain

Indraneel Ghosh

Churl Min Seong

Brendan Orner

Lynne Regan

Gang Liu

Richard M Heller

Mark Jeffrey Jaroszeski

Richard A Gilbert

Hua Yu

Hairuo Peng

William L Jorgensen

William S Dalton

Greg B Donner

Bruce G Szczepankiewicz

Bryan K Sorenson

Yoshitomo Hamuro

Juliana Ruiz-Caro

M Scott Goodman

Jorge Becerril

Mazin Magzoub

Sarah Hassan

James I Wasick

Bernard G Donner

John J Larsen

Stephen J O'CONNOR

Rishi Jain

The invention relates to compounds and pharmaceutical compositions capable of treating amyloid diseases and other diseases characterized by oligomerization and/or fibrillation of amyloidogenic peptides such as islet amyloid polypeptide (IAPP).

Oligopyrroles as antagonists of islet amyloid polypeptide oligomerization

Methods of inducing tumor regression, inhibiting tumor growth, and inducing apoptosis with selective peptidomimetic inhibitors of geranylgeranyltransferase I (GGTase I), are provided. In one aspect, GGTI-2418 and its methylester GGTI-2417, increase levels of the cyclin-dependent kinase (Cdk) inhibitor p27and induce breast tumor regression in vivo. In another aspect, GGTI-2417 inhibits the Cdk2-mediated phosphorylation of p27at Thr187 and accumulates p27in the nucleus.

Methods for inducing tumor regression, inhibiting tumor growth, and inducing apoptosis in breast tumors with geranylgeranyltransferase I inhibitors

The invention relates to compounds and pharmaceutical compositions capable of treating amyloid diseases and other diseases characterized by oligomerization and/or fibrillation of amyloidogenic peptides such as amyloid beta peptide (Abeta or A&#x3b2;).

Alpha-helix mimetics as modulators of Abeta self-assembly

The invention relates to oligopyridylamide alpha-helix mimetic compounds and their use to inhibit p53 aggregation and restore its tumor suppressor function for treating diseases, e.g., cancers, associated with p53 mutations, e.g., R248W p53 mutation.

Use of oligopyridylamides to inhibit mutant p53 amyloid formation and restore its tumor suppressor function

Disclosed herein is a species of peptide and non-peptide inhibitors of Akt, an oncogenic protein. Beginning with a residue of Akt target substrate GSK-3, the functional domains of the GSK-3 residue were characterized. Functionally homologous non-peptide groups were substituted for the amino acids of the GSK-3 creating a hybrid peptide-non-peptide and non-peptide compounds capable of binding to Akt. The non-peptide compounds show increased stability and rigidity compared to peptide counterparts and are less susceptible to degradation. The bound non-peptide compounds exhibit an inhibitory effect on Akt, similar to peptide-based Akt inhibitors.

Substrate-mimetic AKT inhibitor

Substrate-mimetic Akt inhibitor

Signal Transducer and Activator of Transcription (STAT) proteins have a fundamental role cell signaling, and are activated by a large number of cytokines and growth factors. One member of the STAT family, STAT3, has a critical role in oncogenesis. The present invention relates generally to disruption of the pathway of STAT3 signaling in the treatment of human cancer. STAT3 activation is shown to be present in diverse tumor cell lines and tumors, to promote oncogenesis, to inhibit apoptosis, and to reduce sensitivity to chemotherapeutic agents. Inhibition of STAT3 signaling induces apoptosis specifically in tumor cell lines, and increases sensitivity to chemotherapeutic agents. The invention relates more particularly to methods, compositions, means of administering such compositions, and means for identifying such compositions for the inhibition of STAT3 intracellular signaling in the treatment of human cancers.

Inhibition of STAT3 signal transduction for human cancer therapy

Many GTPases such as Ras, Ral and Rho require post-translational farnestylation or geranylgeranylation for mediating malignant transformation. Dual farnesyltransferase (FT) (FTI) and geranylgeranyltransferase-I (GGT-1) inhibitors (GGTI) were developed as anticancer agents from based on an ethylenediamine scaffold. On the basis of a 4-fold substituted ethylenediamine scaffold, the inhibitors are structurally simple and readily derivatized, facilitating extensive structure-activity relationship studies. The most potent inhibitor is compound exhibited an in vitro hFTase ICvalue of 25 nM and a whole cell H-Ras processing ICvalue of 90 nM. Several of the inhibitors proved highly selective for hFTase over the related prenyltransferase enzyme geranylgeranyltransferase-I (GGTase-I). A crystal structure of an inhibitor cocrystallized with farnesyl pyrophosphate in the active site of rat FTase illustrates that the para-benzonitrile moiety is stabilized by a &#x3c0;-&#x3c0; stacking interaction with the Y361&#x3b2; residue, suggesting an importance of this component of the inhibitors.

Dual inhibitors of farnesyltransferase and geranylgeranyltransferase I

The present invention relates to compounds according to the formula I: Where Ris H or an optionally OH-substituted C-Calkyl; Ris OR, an optionally substituted Ccarbocyclic group which may be saturated or unsaturated (including aromatic) or an optionally substituted heterocyclic group; Ris an optionally substituted C-Chydrocarbyl group or an optionally substituted heterocyclic group; R, Rand Rare each independently H, an optionally substituted C-Calkyl group (preferably CH, CHCHor CF), halogen (preferably F, Cl, Br), OR, CN, NO, a C-Cthioether, a C-Cthioester group, an optionally substituted COR group, an optionally substituted COR group or an optionally substituted OCOR group (preferably Ris H); R is H or an optionally substituted C-Calkyl group; RHET is an optionally substituted heterocyclic group; and pharmaceutically acceptable salts, solvates or polymorphs thereof. 

Compounds and methods for the treatment of viruses and cancer

The subject invention concerns compositions and methods for blocking cancer cell growth or proliferation and/or inducing cancer cell death. Compositions of the present invention are compounds that inhibit Rho-protein associated kinase function. Compounds of the invention include piperazinyl pyridines, piperazinylmethyl pyridines, piperazinyl ureas and carbamates, piperazinyl pyridines and quinoilines (including isoquinliones) as well as piperazinyl (including piperazinylmethyl) pyridines and quinolines (including isoquinolines). Compounds of the invention disrupt Rho-kinase activation and function and significantly inhibit tumor cell growth and induce tumor cell death.

Rock inhibitors and uses thereof

Disclosed herein are compounds derived from a chemical structure according to the formula (I) wherein X comprises oxygen or sulfur, Rcomprises a phenyl or naphthyl group, Rcomprises an amide group and Rcomprises a phosphate group. The disclosed compounds demonstrate inhibitory activity against STAT3, a protein found in certain tumor tissues and which promotes cellular overproliferation and resistance to apoptosis. The invention includes compositions containing the disclosed compounds, as well as methods of treatment therewith. 

Inhibitors of STAT3

A small-molecule Stat3 dimerization inhibitor, S3I-M2001, is described and the dynamics of intracellular processing of activated Stat3 within the context of the biochemical and biological effects of the Stat3 chemical probe inhibitor are elucidated. S3I-M2001 is a newly-identified oxazole-based peptidomimetic of the Stat3 Src Homology (SH) 2 domain-binding phosphotyrosine peptide that selectively disrupts active Stat3:Stat3 dimers. Stat3-dependent malignant transformation, survival, and migration and invasion of mouse and human cancer cells harboring persistently-activated Stat3 were inhibited by S3I-M2001. S3I-M2001 inhibited Stat3-dependent transcriptional regulation of tumor survival genes, such as Bcl-xL. The disclosed compound is useful as a new potential treatment for certain cancers.

Stat3 inhibitor having anti-cancer activity and methods

Growth factor binding molecules having a plurality of peptide loops attached to a non-peptide organic scaffold, preferably having pseudo-six amino acid peptide loops with four amino acid sidechains. The growth factor binding molecules specifically bind various growth factors and are suitable for treating a subject having tumors or restinosis. In one embodiment a platelet-derived growth factor binding molecule is disclosed that is used to inhibit tumor growth and angiogenesis in solid tumors.

Growth factor binding molecules

The subject invention concerns compositions and methods for blocking cancer cell growth or proliferation and/or inducing cancer cell death. Compositions of the present invention are peptidomimetics that inhibit STAT function. Peptidomimetics of the invention display selective inhibition of specific STAT isoform homo-dimerization. The peptidomimetic probes of STAT1 function, described herein, provide the means to preferentially inhibit STAT1 over STAT3 through the exploration of the C-terminus.

Use of SH2 STAT3/STAT1 peptidomimetics as anticancer drugs

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New York, NY, United States of America

Andrew D Hamilton