Small molecule inhibitors of lactate dehydrogenase and methods of use thereof
Inventors
Maloney, David J. • Waterson, Alex Gregory • Bantukallu, Ganesh Rai • Brimacombe, Kyle Ryan • Christov, Plamen • Dang, Chi V. • Darley-Usmar, Victor • Hu, Xin • Jadhav, Ajit • Jana, Somnath • Kim, Kwangho • Kouznetsova, Jennifer L. • Moore, William J. • Mott, Bryan T. • Neckers, Leonard M. • Simeonov, Anton • Sulikowski, Gary Allen • Urban, Daniel Jason • Yang, Shyh Ming
Assignees
UAB Research Foundation • University of Pennsylvania Penn • Vanderbilt University • US Department of Health and Human Services
Publication Number
US-11247971-B2
Publication Date
2022-02-15
Expiration Date
2035-12-29
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Abstract
Provided is a compound of formula (I), in which Ar1, R1, 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.
Core Innovation
The invention provides compounds of formula (I), including specific subformulae such as formulas (Ia), (Ib), (Ic), and (Id), which are effective in inhibiting lactate dehydrogenase A (LDHA) and/or lactate dehydrogenase B (LDHB) activity. The compounds have various substituents and structural features that confer selectivity and potency. They tend to be selective for LDHA and/or LDHB relative to other dehydrogenases and have desired solubility, permeability, and pharmacokinetic profiles suitable for anti-cancer agents.
The problem addressed by this invention arises from the need for novel inhibitors of LDHA and/or LDHB that have improved potency, selectivity, and bioavailability for the treatment of cancer. Previous known LDHA inhibitors, such as gossypol and certain quinolinyl derivatives, suffered from poor bioavailability and lack of selectivity. Cancer tissues rely heavily on aerobic glycolysis, with LDH catalyzing the conversion of pyruvate to lactate, a key step in cancer cell metabolism. Inhibition of LDH is expected to reduce tumor growth, thus necessitating the development of more effective LDH inhibitors with better properties.
The invention also discloses methods of using the compounds of formula (I) in treating cancer, treating patients with cancer cells resistant to anti-cancer agents, and treating fibrosis including idiopathic pulmonary fibrosis. The compounds can be administered alone or in combination with anti-cancer agents to sensitize resistant cancer cells. Pharmaceutical compositions and administration routes are detailed with an emphasis on oral and intravenous administration.
Claims Coverage
The patent document contains multiple independent claims including claim 1 directed to a compound of formula (Ia) with specific substituents and structures. Subsequent claims depend on claim 1 and specify particular embodiments or substructures.
small molecule inhibitors of lactate dehydrogenase a/b
A compound of formula (Ia) selectively inhibiting LDHA and/or LDHB, having defined substituents such as R1 independently chosen from various groups including halo, hydroxyl, sulfonamides and others, R2 including sulfonamide substituents, and structural features such as X being —CR8R9—, —O—, or —NH—. The compounds include pharmaceutically acceptable salts and prodrugs and are selected for their ability to modulate LDHA/LDHB activities.
specific substituents for improved selectivity and bioavailability
Compounds where R1, R2, R3, and other substituents are chosen from specific groups to confer desired pharmacological properties including potency, selectivity and ADME characteristics, with examples including halogen, alkyl, alkenyl, alkoxy, sulfonamide, and heterocyclic moieties.
pharmaceutical compositions and treatment methods
Methods of treating cancer, fibrosis including idiopathic pulmonary fibrosis, and patients with cancer cells resistant to anti-cancer agents through administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or prodrug. The administration can be oral, intravenous, or other known routes and can be in combination with other anti-cancer agents.
The claims collectively cover novel compounds of formula (Ia) and their pharmaceutically acceptable salts and prodrugs that inhibit LDHA and/or LDHB with improved potency and selectivity, pharmaceutical compositions containing these compounds, and methods for treating cancer and fibrosis by administering these compounds.
Stated Advantages
Selective inhibition of LDHA and/or LDHB relative to other dehydrogenases.
Potential to reduce tumor cell proliferation and tumor growth by inhibiting cancer cell metabolism.
Improved potency and bioavailability over previously known LDH inhibitors.
Capability to resensitize cancer cells resistant to anti-cancer agents.
Desirability for treating fibrosis, including idiopathic pulmonary fibrosis.
Documented Applications
Treatment of cancer including solid tumors, sarcomas, carcinomas, leukemias, and other cancers characterized as hypoxic and/or highly glycolytic.
Treatment of fibrosis including idiopathic pulmonary fibrosis.
Treatment of patients with cancer cells resistant to anti-cancer agents, optionally in combination with chemotherapy or radiation therapy.
Inhibition of LDHA and/or LDHB activity in cells.
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