National Institutes of Health, a Component of the US Dept. of Health & Human Services

University of Pennsylvania

Vanderbilt University

The Uab Research Foundation

University of California

Thomas Jefferson University

Eastern Virginia Medical School

Other

University of North Carolina at Chapel Hill

Convergene, LLC

The United States of America Department of Health

Washington University

University of Delaware

Children's Hospital

The General Hospital Corporation

Ajit Jadhav

David Joseph Maloney

Anton Simeonov

Daniel Jason Urban

Shyh Ming Yang

Kyle Ryan Brimacombe

Diane K Luci

Alex Gregory Waterson

William J Moore

Gary Allen Sulikowski

Kwangho Kim

Leonard M Neckers

Xin Hu

Plamen P Christov

Victor M Darley-Usmar

Somnath Jana

Bryan T Mott

Chi V Dang

Ganesh Rai Bantukallu

Jennifer L Kouznetsova

Theodore Holman

Thomas S Dexheimer

David A Taylor-Fishwick

Michael Holinstat

Adam Yasgar

Steven McKenzie

Jerry L Nadler

Elias Set Jenö Arnér

William Chester Stafford

Nathan Patrick Coussens

Li Liu

Xiaodong Wang

Matthew E Hall

Min Shen

Matthew Brian Boxer

Andrew Louis McIver

Jeffrey William Strovel

Jason Matthew Rohde

Makoto Yoshioka

Rajan Pragani

Mindy Irene Emily Davis

Ganesha Rai Bantukallu

Surendra Karavadhi

Shyh-Ming Yang

Fumihiko Urano

Yu Liang

Thomas Kristie

Natalia Martinez

Zhihao Zhuang

Jodi Vogel

David Maloney

Yuhong Fang

Mark Henderson

Brandon Harvey

Amy Clark

Jana Mahadevan

Qin Liang

Andrew S Rosenthal

Ganesha Rai

Klaus Joachin Van Leyen

Wei Zhao

Klaus Van Leyen

Steven E Mckenzie

Theodore R Holman

David J Maloney

Matthew Hall

Brian T Mott

Provided is a compound of formula (I) in which Ar, R, U, V, W, X, and p are as described herein. Also provided are methods of using a compound of formula (I), including a method of treating cancer, a method of treating a patient with cancer cells resistant to an anti-cancer agent, and a method of inhibiting lactate dehydrogenase A (LDHA) and/or lactate dehydrogenase B (LDHB) activity in a cell.

Small molecule inhibitors of lactate dehydrogenase and methods of use thereof

The present invention generally relates to compositions and methods for treating or preventing an endoplasmic reticulum stress disorder in subjects, including compositions and methods for treating or preventing Wolfram syndrome. The present invention also relates to methods for treating symptoms of neurodegenerative diseases.

Treatment for Wolfram syndrome and other endoplasmic reticulum stress disorders

Human lipoxygenases (LOXs) are a family of iron-containing enzymes involved in catalyzing the oxidation of polyunsaturated fatty acids to provide the corresponding bioactive hydroxyeicosatetraenoic acid (HETE) metabolites. These eicosanoid signaling molecules are involved in a number of physiologic responses such as platelet aggregation, inflammation, and cell proliferation. Platelet-type 12-(S)-LOX (12-LOX) is of particular interest because of its demonstrated role in skin diseases, diabetes, platelet hemostasis, thrombosis, and cancer. Disclosed herein is the identification and medicinal chemistry optimization of a 4-((2-hydroxy-3-methoxybenzyl)amino)benzenesulfonamide-based scaffold. The compounds display nM potency against 12-LOX and excellent selectivity over related lipoxygenases and cyclooxygenases. In addition to possessing favorable ADME properties, the compounds also inhibit PAR-4 induced aggregation and calcium mobilization in human platelets, and reduce 12-HETE in mouse/human beta cells. The compounds can also be used in methods for treating or preventing a 12-lipoxygenase mediated disease or disorder.

4-((2-hydroxy-3-methoxybenzyl)amino)benzenesulfonamide derivatives as potent and selective inhibitors of 12-lipoxygenase

Provided is a compound of formula (I), in which Ar, R, U, V, W, X, and p are as described herein. Also provided are methods of using a compound of formula (I), including a method of treating cancer, a method of treating a patient with cancer cells resistant to an anti-cancer agent, and a method of inhibiting lactate dehydrogenase A (LDHA) and/or lactate dehydrogenase B (LDHB) activity in a cell.

There is provided compounds of formula (I) or pharmaceutically-acceptable salts thereof, wherein W, X, Y, Z, R, Rand Rhave meanings provided in the description, which compounds are useful in the treatment of cancers. 

Pyridazinones and their use in the treatment of cancer

The present invention relates to compounds that bind to and otherwise modulate the activity of bromodomain-containing proteins, to processes for preparing these compounds, to pharmaceutical compositions containing these compounds, and to methods of using these compounds for treating a wide variety of conditions and disorders.

Small molecule BET bromodomain inhibitors and uses thereof

The disclosure provides a compound of the formula (II) and pharmaceutically acceptable salts thereof. The variables, e.g. n, R, R, R, X, Y, and Z are defined herein. These compounds act as lactate dehydrogenase inhibitors and are useful for treating cancer and fibrosis. The compounds may be particularly useful for treating forms of cancer in which a metabolic switch from oxidative phosphorylation to glycolysis has occurred. The disclosure also provides pharmaceutical compositions containing a compound of this formula and method for treating patients having cancer, fibrosis, or other conditions in which a metabolic switch from oxidative phosphorylation to glycolysis has occurred. 

1 H-pyrazol-1-yl-thiazoles as inhibitors of lactate dehydrogenase and methods of use thereof

There is provided compounds of formula (I) or pharmaceutically-acceptable salts thereof, wherein L, R, R, R, Rand n have meanings provided in the description, which compounds are useful in the treatment of cancers. 

Pyridines and their use in the treatment of cancer

There is provided compounds of formula (I), or pharmaceutically-acceptable salts thereof, wherein X, Y, Z, Rand Rhave meanings provided in the description, which compounds are useful in the treatment of cancers. 

Tricyclic compounds and their use in the treatment of cancer

A compound of Formula II or a pharmaceutically acceptable salt thereof, wherein CyN is a cyclic amine group bound via a nitrogen atom; X is C or N; Rand Rare each independently a halogen, CN, CF, CHF, CHF, a C-C10alkyl group, a C1-Calkoxy group, a di(C-Calkyl)amino; m and n are each independently 1, 2, or 3, and represents either a single bond or a double bond, wherein the racemic mixture of 3-(4-(4-chlorophenyl)thiazol-2-yl)-1-(2-ethyl-5-methoxyphenyl)-6-(2-methylprop-1-en-1-yl)-5-(piperazine-1-carbonyl)pyridin-2(1H)-one atropisomers is excluded.

Thiazole derivatives useful as mutant IDH1 inhibitors for treating cancer

Compounds of Formula I and Formula II and the pharmaceutically acceptable salts thereof are disclosed The variables A, B, Y, Z, X, X, Rand Rare disclosed herein. The compounds are useful for treating cancer disorders, especially those involving mutant IDH1 enzymes. Pharmaceutical compositions containing compounds of Formula I or Formula II and methods of treatment comprising administering compounds of Formula I and Formula II are also disclosed. 

Mutant IDH1 inhibitors useful for treating cancer

The present invention relates to compounds that bind to and otherwise modulate the activity of bromodomain-containing proteins, to processes for preparing these compounds, to pharmaceutical compositions containing these compounds, and to methods of using these compounds for treating a wide variety of conditions and disorders. 

Bicyclic BET bromodomain inhibitors and uses thereof

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Chantilly, VA, United States of America

Ajit Jadhav