Massachusetts Institute of Technology

University of Washington

University of Massachusetts

Yale University

Darwin Molecular Corporation

John M Essigmann

Robert G Croy

Stephen J Lippard

Patti Jean Kellett

Jeffrey H Toney

Brian A Donahue

Pieter M Pil

Suzanne L Bruhn

Steven J Brown

Marshall Morningstar

Kevin J Yarema

Lawrence A Loeb

Bogdan I Fedeles

Andrei Tokmakoff

Stefan Somlo

Steven Joel Brown

Chunte Peng

Sorin V Fedeles

Deyu Li

Zhenghuan Chen

Katherine J Silvestre

Doriana Froim

Vipender Singh

Martin G Marinus

The present invention provides compounds of Formula (I) or (II), which are thought to be able to inhibit mTOR (mammalian target of rapamycin) signaling pathway, induce UPR (unfolded protein response), and/or perturb mitochondrial function of a cyst cell (e.g., a cyst cell causing polycystic kidney disease (PKD, e.g., autosomal dominant PKD (ADPKD) or autosomal recessive PKD (ARPKD)) or polycystic liver disease (PLD, e.g., autosomal dominant PLD (ADPLD) or autosomal recessive PLD (ARPLD)). The invention also provides pharmaceutical compositions, kits, and methods involving the compounds described herein for use in treating PKD or PLD, inhibiting the growth of a cyst cell, and/or killing a cyst cell. 

Methods for treating polycystic kidney disease and polycystic liver disease

The present disclosure provides nucleoside analogs of Formula (I) or (II). The nucleoside analogs are expected to show multiple tautomerism and may increase the mutation of an RNA and/or DNA (be mutagenic) of a virus or cancer cell. The multiple tautomerism and mutagenesis of the nucleoside analogs may be adjusted by substituting the nucleoside analogs with one or more electron-donating groups and/or electron-withdrawing groups to increase or decrease the pK(e.g., to a pKbetween 5.5 or 8.5). The present disclosure also provides pharmaceutical compositions and kits including the nucleoside analogs and methods of treating a viral infection (e.g., influenza, HIV infection, or hepatitis) or cancer using the nucleoside analogs, pharmaceutical compositions, or kits.

Mutagenic nucleoside analogs and uses thereof

The present invention provides pharmaceutical compositions comprising a dihydro base described herein (e.g., compound DHdC). The dihydro base may show multiple tautomerism and may increase mutation of an RNA and/or DNA of a virus or cancer cell. The dihydro base may be used to reduce DNA methylation (e.g., in a cancer cell). The present invention also provides kits including the inventive pharmaceutical compositions and methods of treating a viral infection (e.g., influenza, HIV infection, or hepatitis C) or cancer using the pharmaceutical compositions or kits. 

Uses of dihydro bases

This invention provides methods and pharmaceutical compositions for treating a subject having a condition associated with an antibiotic resistant bacterial infection. The invention includes administering to a subject a therapeutically effective combination of an antibiotic and a toxic compound (e.g., a nucleic acid damaging agent, an alkylating agent, or a heavy metal containing compound).

Antimicrobial combination therapy

The compositions and methods disclosed herein provide heterobifunctional programmable genotoxic compounds that can be designed to kill selected cells present in a heterogenous cell population. The present compounds comprise a first agent that inflicts damage on cellular DNA, and a second agent that attracts a macromolecular cell component such as a protein, which in turn shields genomic lesions from repair. Unrepaired lesions therefore persist in the cellular genome and contribute to the death of selected cells. In contrast, lesions formed in nonselected cells, which lack the cell component, are unshielded and thus are repaired. As a result, compounds described herein are less toxic to nonselected cells. Compounds of this invention can be designed to cause the selective killing of transformed cells, viral-infected cells and the like.

Programmable genotoxic agents and uses therefor

Methods disclosed herein capitalize on the ability of DNA Structure Specific Recognition Proteins (SSRPs) to bind to genomic lesions formed by chemotherapeutic agents, particularly cisplatin-type agents. Methods are provided for predicting whether an agent that damages DNA will also be cytotoxic, and for predicting whether particular eukaryotic cells will be susceptible to killing by a genotoxic drug. A screening method is provided for identifying new genotoxic drugs that produce SSRP-recognized lesions in DNA. Methods also are provided for sensitizing particular eukaryotic cells to killing by chemotherapeutic agents, particularly cisplatin-type drugs.

Uses for DNA structure-specific recognition protein

Methods and compositions related to HIV are disclosed. Using the methods of the present invention, nucleoside analogs may be screened for the ability to be incorporated by reverse transcriptase of human immunodeficiency virus ('HIV RT') and cause incorrect base pairing. Progressive mutation of the virus by such nucleoside analogs renders it non-viable.

Methods of screening for nucleoside analogs that are incorporated by HIV

DNA structure specific recognition protein of eukaryotic origin and DNA encoding such a factor, as well as probes specific for DNA structure specific recognition protein or DNA encoding it and methods of detecting DNA structure specific recognition protein in eukaryotic cells. In particular, a mammalian cellular factor that selectively recognizes and binds DNA damaged or modified by a drug (the anticancer drug, cis-diamminedichloroplatinum (II) or cisplatin) has been identified.

DNA structure specific recognition protein complexes

Nucleic acids encoding DNA structure-specific recognition protein and

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Cambridge, MA, United States of America

John M Essigmann