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-12365653-B2
Publication Date
2025-07-22
Expiration Date
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
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 present invention provides a compound of formula (I) in which Ar1, R1, U, V, W, X, and p are as described herein. It has been discovered that a compound defined by formula (I) is effective in inhibiting lactate dehydrogenase A (LDHA) and/or lactate dehydrogenase B (LDHB) activity, thereby making the compound effective in treating cancer. The disclosure further provides a method of treating cancer in a patient comprising administering to the patient an effective amount of the compound of formula (I) or a prodrug or a pharmaceutically acceptable salt thereof.
Agents that target enzymes involved in cancer cell metabolism offer an attractive therapeutic route in view of the potential to preferentially target cancer tissue over normal tissue. Lactate dehydrogenase (LDH) is involved in the final step of glycolysis, in which pyruvate is converted to lactate, and inhibition of LDH is expected to reduce the ability of the cell to effectively metabolize glucose and reduce tumor cell proliferation and tumor growth. In view of the foregoing, there remains a need to provide novel LDH inhibitors with improved potency, selectivity, and/or bioavailability for the treatment of cancer.
Claims Coverage
Overview: The patent includes one independent claim directed to a compound of formula (Ia-1).
Compound of formula (Ia-1)
The compound or pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (Ia-1).
Conclusion: The independent claim is directed to a compound of formula (Ia-1) and pharmaceutically acceptable salts thereof.
Stated Advantages
Effective in inhibiting lactate dehydrogenase A (LDHA) and/or lactate dehydrogenase B (LDHB) activity.
Effective in treating cancer.
Useful for treating fibrosis, including idiopathic pulmonary fibrosis.
Tends to be selective for LDHA and/or LDHB relative to other dehydrogenases (e.g., GAPDH and PHGDH).
Tends to have a desired solubility, permeability, and/or pharmacokinetics profile (e.g., ADME) for an anti-cancer agent.
Re-sensitizes cancer cells to an anti-cancer agent when co-administered, thereby treating cancer cells resistant to an anti-cancer agent.
Documented Applications
A method of treating cancer in a patient comprising administering to the patient an effective amount of the compound of formula (I) or a prodrug or a pharmaceutically acceptable salt thereof.
A method of treating fibrosis, including idiopathic pulmonary fibrosis, in a patient comprising administering to the patient an effective amount of the compound of formula (I) or a prodrug or a pharmaceutically acceptable salt thereof.
A method of treating a patient with cancer cells resistant to an anti-cancer agent, comprising administering to the patient an effective amount of the compound of formula (I) or a prodrug or a pharmaceutically acceptable salt thereof, and the anti-cancer agent, whereby the compound, prodrug, or pharmaceutically acceptable salt thereof re-sensitizes the cancer cells to the anti-cancer agent.
A method of inhibiting lactate dehydrogenase A (LDHA) and/or lactate dehydrogenase B (LDHB) activity in a cell comprising administering a compound of formula (I) or a prodrug or a pharmaceutically acceptable salt thereof to a cell.
Pharmaceutical compositions comprising a compound of formula (I) or a prodrug or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, and administration routes including oral or intravenous administration as described in the disclosure.
Co-administration (simultaneous or sequential) of a compound of formula (I), prodrug, or pharmaceutically acceptable salt thereof with one or more anti-cancer agents and/or radiation therapy to sensitize cancer cells to therapeutic regimens.
Interested in licensing this patent?