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.

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

Institute of Organic Chemistry & Biochemistry

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

Lukas Tenora

Barbara S Slusher

Pavel Majer

Rana Rais

Andrej Jancarik

Tomas Tichy

Jan Vavra

Jonathan David Powell

Katerina Novotna

Judson Englert

Gregory J Riggins

Ivan Snajdr

Robert Leone

Andrei Jancarik

Jesse Alt

Peter Michael Hudlicky

Diane E Peters

Jonathan Powell

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

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

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

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

Prodrug compositions and utility of hydroxamate-based GCPII inhibitors

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.

Growing community of inventors

Prague, Czechia

Lukas Tenora