Guilford Pharmaceuticals, Inc.

The Johns Hopkins University

ÚStav Organické Chemie A Biochemie Av {Hacek Over (c)}r, V.v.i.

Institute of Organic Chemistry and Biochemistry Ascr, V.v.i.

Institute of Organic Chemistry & Biochemistry

Icahn School of Medicine at Mount Sinai

Eisai Inc.

Ustav Organicke Chemie a Biochemie Av Cr, V.v.i.

Eisai Corporation of North America

Inst of Organic Chem. and Biochemistry As Cr V.v.i

ÚStav Organické Chemie A Biochemie Av {Hacek Over (c)}{hacek Over ( )}R, V.v.i.

Adarga Limited

Barbara S Slusher

Paul F Jackson

Keith M Maclin

Pavel Majer

Kevin L Tays

Rana Rais

Takashi Tsukamoto

Andrej Jancarik

Lukas Tenora

Camilo Rojas

Tomas Tichy

Eric Yanjun Wang

Rena S Lapidus

Marcela Krecmerova

Doris Stoermer

Jonathan David Powell

Norman J Haughey

Jan Vavra

Dana Victor Ferraris

Xuhang Li

Justin Scot Hanes

Joseph P Steiner

Gregory J Riggins

Donald Jeffrey Zack

Xin Hu

James Inglese

Marc Ferrer

Tomas Vojkovsky

Jie Fu

Bridget Duvall

Zhiyong Yang

Cynthia Ann Berlinicke

James Vornov

Qingguo Xu

Ivan Snajdr

Krystyna Wozniak

Ajit G Thomas

Xi-Chun May Lu

Niyada Hin

Anne Le

Katerina Novotna

Robert Leone

Judson Englert

Weixing Li

Michal Sala

Adam Kaplin

David Volsky

Kristen A Rahn

Mike Nedelcovych

Kristen Hollinger

Atsushi Kamiya

Laszlo Hackler

Jesse Alt

Michael Polydefkis

Marigo Stathis

Radim Nencka

Hubert Hrebabecky

Andrei Jancarik

Yao-Sen Ko

Peter Michael Hudlicky

Ondrej Stepanek

Michael Nedelcovych

Diane E Peters

Jonathan Powell

Michal SÁLA

Clemens Kratochwil

Glutamine antagonists and their use for treating oncological, immunological, and neurological diseases are disclosed. Also disclosed are methods for treating an oncological, immunological, infectious or neurological disease or disorder, the method comprising administering to a subject in need of treatment thereof a therapeutically effective amount of a glutamine antagonist of the disclosure or the pharmaceutical composition thereof. Also disclosed are methods of enhancing the effects of an immune checkpoint inhibitor, enabling a subject to respond to an immune checkpoint inhibitor, or enabling the toxicity or the dose or number of treatments with an immune checkpoint inhibitor to be reduced, comprising administering to a subject in need of treatment thereof a therapeutically effective amount of a glutamine antagonist of the disclosure or the pharmaceutical composition thereof, and an immune checkpoint inhibitor. Also disclosed are methods for treating an oncological, immunological, infectious or neurological disease or disorder that is refractory to checkpoint inhibitor therapy, the method comprising administering to a subject in need thereof, and having the refractory disease or disorder, a therapeutically effective amount of a glutamine antagonist of the disclosure or the pharmaceutical composition thereof.

Glutamine antagonists and uses thereof

Small molecule inhibitors of neutral sphingomyelinase 2 (nSMase2) and their use for treating neurodegenerative diseases, such as, neurodegenerative diseases associated with high levels of ceramide, including, but not limited to Alzheimer's disease (AD), HIV-associated neurocognitive disorder (HAND), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS), and, in other aspects, for treating cancer or HIV-1, are provided.

Small molecule neutral sphingomyelinase 2 (nSMase2) inhibitors

Methods and compounds are disclosed for treating a disease or condition by inhibiting PSMA (Prostate Specific Membrane Antigen) using prodrugs of 2-PMPA.

Prodrugs of prostate specific membrane antigen (PSMA) inhibitor

The disclosure provides compounds having formula (I): and the pharmaceutically acceptable salts thereof, wherein R, R, R′, and X are as defined as set forth in the specification. Compounds having formula (I) are prodrugs that release glutamine analogs, e.g., 6-diazo-5-oxo-L-norleucine (DON). The disclosure also provides compounds having formula (I) for use in treating cancer.

Prodrugs of glutamine analogs

Prodrugs of hydroxamate-based GCPII inhibitors and methods of their use for treating a disease or condition are disclosed.

Prodrugs of hydroxamate-based GCPII inhibitors

Methods for treating one or more diseases associated with neutral sphingomyelinase 2 (nSMase2) in a subject in need of treatment thereof, the method comprising administering to the subject a therapeutically effective amount of 2,6-dimethoxy-4-(5-phenyl-4-thiophen-2-yl-1H-imidazol-2-yl)-phenol (DPTIP) or a pharmaceutically acceptable salt thereof, are disclosed.

2,6-dimethoxy-4-(5-phenyl-4-thiophene-2-yl-1H-imidazol-2-yl)-phenol (DPTIP) a small molecule inhibitor of neutral sphingomyelinase 2 (nSMase-2) for the treatment of neurodegenerative and oncologic diseases

Methods for treating a Human Immunodeficiency Virus (HIV) infection comprising administering to a subject in need of treatment thereof an effective amount of a small molecule nSMase2 inhibitor.

Inhibition of nSMase for the treatment of human immunodeficiency virus infection

The disclosure provides methods of treating cancer in a subject or preventing a relapse or reducing the incidence of relapse of cancer in a subject in remission, comprising administering to the subject: (a) a therapeutically effective amount of an immunotherapeutic agent, e.g., an immune checkpoint blockade therapy, an adoptive cellular therapy, a marrow-infiltrating lymphocytes, an adenosine A2aR inhibitor, or an antibody; and (b) a compound having formula (I): and the pharmaceutically acceptable salts thereof, wherein R, R, R', and X are as defined as set forth in the specification. Compounds having formula (I) are prodrugs that release glutamine analogs, e.g., 6-diazo-5-oxo-L-norleucine (DON).

Methods for cancer and immunotherapy using prodrugs of glutamine analogs

Prodrugs of mebendazole and methods for their use in treating a disease, disorder, or disorder, including cancer, are disclosed.

Mebendazole prodrugs with enhanced solubility and oral bioavailability

Small molecule inhibitors of neutral sphingomyelinase 2 (nSMase2) and their use for treating neurodegenerative diseases, such as, neurodegenerative diseases associated with high levels of ceramide, including, but not limited to Alzheimer's disease (AD), HIV-associated neurocognitive disorder (HAND), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS), and, in other aspects, for treating cancer, are provided.

Small molecule inhibitors of neutral sphingomyelinase 2 (nSMase2) for the treatment of neurodegenerative diseases

Methods for buccally, sublingually, or intranasally administering a prodrug of propofol to a subject in need of treatment thereof in an amount sufficient to deliver a therapeutically effective amount of propofol to the subject are disclosed.

Buccal, sublingual and intranasal delivery of fospropofol

Currently available glutaminase inhibitors are generally poorly soluble, metabolically unstable, and/or require high doses, which together reduce their efficacy and therapeutic index. These can be formulated into nanoparticles and delivered safely and effectively for treatment of pancreatic cancer and other glutamine addicted cancers. Studies demonstrate that nanoparticle delivery of BPTES, relative to use of BPTES alone, can be safely administered and provides dramatically improved tumor drug exposure, resulting in greater efficacy. GLS inhibitors can be administered in higher concentrations with sub-100 nm nanoparticles, since the nanoparticles package the drug into 'soluble' colloidal nanoparticles, and the nanoparticles deliver higher drug exposure selectively to the tumors due to the enhanced permeability and retention (EPR) effect. These factors result in sustained drug levels above the IC50 within the tumors for days, providing significantly enhanced efficacy compared to unencapsulated drug.

Glutaminase inhibitor discovery and nanoparticle-enhanced delivery for cancer therapy

Prodrugs of glutamine analogs, such as prodrugs of acivicin, are disclosed.

The disclosure provides compounds having formula (I): and the pharmaceutically acceptable salts thereof, wherein R, R, R', and X are as defined as set forth in the specification, for use in treating cognitive deficits and/or psychiatric disorders, such as those associated with neurological or neurodegenerative disorders, psychiatric or mood disorders, and HIV-associated neurocognitive disorders (HAND). Compounds having formula (I) are prodrugs that release glutamine analogs, e.g., 6-diazo-5-oxo-L-norleucine (DON).

Glutamine antagonists for the treatment of cognitive deficits and psychiatric disorders

Growing community of inventors

Kingsville, MD, United States of America

Barbara S Slusher