The Scripps Research Institute

University of Florida Research Foundation Inc

John L Cleveland

Thomas D Bannister

William R Roush

Andy Tsai

Hui Wang

Chao Wang

Jitendra K Mishra

Jun Yong Choi

Reji Nair

Derek R Duckett

Laura H Rosenberg

Andy S Tsai

The invention provides compounds of formulae A, B, and C as described herein that inhibit monocarboxylate transporters, such as MCT1 and MCT4. Compounds of the invention can be used for treatment of a condition in a patient, wherein the condition is characterized by the heightened activity or by the high prevalence of MCT1 and/or MCT4, such as cancer or type II diabetes.

Heterocyclic inhibitors of monocarboxylate transporters

The invention provides compounds effective as inhibitors of monocarboxylate transporters such as MCT1 and MCT4, which can be used for treatment of medical conditions wherein treatment of the condition with a compound having an inhibitor effect on MCT1, MCT4, or both is medically indicated. Compounds of the invention can have antitumor, antidiabetes, anti-inflammatory, or immunosuppressive pharmacological effects, and can be effective for treatment of cancer and of type II diabetes.

Pteridine dione monocarboxylate transporter inhibitors

The invention provides heterocyclic compounds of formula A, B, and C as described herein that inhibit monocarboxylate transporters, such as MCT1 and MCT4. Compounds of the invention can be used for treatment of a condition in a patient, wherein the condition is characterized by the heightened activity or by the high prevalence of MCT1 and/or MCT4, such as cancer or type II diabetes.

The invention provides a method of inhibiting casein kinase 1&#x3b4; (CK1&#x3b4;), comprising contacting the CK1&#x3b4; with a compound of formula (I), as defined herein; such as compound SR-3029. We demonstrate that CSNK1D is amplified and/or overexpressed in human breast tumors and that CK1&#x3b4; can be medically targeted in human breast cancer subtypes overexpressing this kinase. The invention further provides a method of treating cancer, such as a breast cancer, melanoma, glioblastoma, medulloblastoma, renal, bladder or colon cancer, or a cancer that metastasizes to the brain, lung, or bone provided that both elevated CK1&#x3b4; and &#x3b2;-catenin dependence are involved in those metastatic diseases. The cancer can be a breast cancer of the triple negative subclass of breast cancers (TNBC), or can be an HER+ breast cancer.

Therapeutic targeting of casein kinase 1&#x3b4; in breast cancer

The invention provides compounds that inhibit monocarboxylate transporters, such as MCT1 and MCT4. Compounds of the invention can be used for treatment of a condition in a patient, wherein the condition is characterized by the heightened activity or by the high prevalence of MCT1 and/or MCT4, such as cancer or type II diabetes.

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Land O Lakes, FL, United States of America

John L Cleveland