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-11897845-B2
Publication Date
2024-02-13
Expiration Date
2035-12-29
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
Agents that target enzymes involved in cancer cell metabolism offer an attractive therapeutic route because cancer tissue relies heavily on aerobic glycolysis regardless of the oxygen supply level, a property known as the Warburg effect. Lactate dehydrogenase (LDH) catalyzes the conversion of pyruvate to lactate, which is vital for tumor growth and survival. Inhibiting LDH is expected to reduce tumor cell proliferation and tumor growth by impairing glucose metabolism.
Previously known LDHA inhibitors, such as gossypol and certain derivatives of 3-((3-carbamoyl-7-(3,5-dimethylisoxazol-4-yl)-6-methoxyquinolin-4-yl) amino) benzoic acid, showed limitations including poor in vivo bioavailability. Therefore, there remains a need to provide novel LDH inhibitors with improved potency, selectivity, and/or bioavailability for cancer treatment.
The invention provides compounds of formula (I) that effectively inhibit LDHA and/or LDHB activity. These compounds tend to be selective for LDHA and/or LDHB relative to other dehydrogenases such as GAPDH and PHGDH. Additionally, they may have desired solubility, permeability, and pharmacokinetics profiles suitable as anti-cancer agents. The invention also includes methods of treating cancer, fibrosis including idiopathic pulmonary fibrosis, and methods of re-sensitizing cancer cells resistant to anti-cancer agents by administering these compounds or their pharmaceutically acceptable salts or prodrugs.
Claims Coverage
The patent contains one independent claim and multiple dependent claims related to compounds of formula (Ib) and their uses.
Compound of formula (Ib)
A compound or pharmaceutically acceptable salt of the specified formula (Ib) characterized by a particular chemical structure with detailed substituent definitions for R1, R3, R5, R6, R10, X1, X2, and X3. These define the core chemical structure and its functional groups.
Specific structural features
Details for substituents including R10 as hydrogen or various substituted/unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, hydroxy, halo, cyano, and heteroarylalkyl moieties; R1 as carboxylic acid or alkyl esters; R3 as halo, haloalkyl, haloalkoxy, or various substituted alkyl/aryl groups; X1 as specific linkers such as —CH2—, —O— or —NH—; and X2 as a sulfur atom.
Pharmaceutical compositions
Pharmaceutical compositions comprising the compound or pharmaceutically acceptable salts thereof with pharmaceutically acceptable carriers.
Methods of treatment
Methods of treating fibrosis or cancer, and methods of treating cancer cells resistant to anti-cancer agents by administering the compound or salt, optionally co-administered with anti-cancer agents to sensitize resistant cells.
The invention claims compounds of formula (Ib) with defined substituents conferring inhibitory activity against LDHA and/or LDHB, pharmaceutical compositions containing such compounds, and methods of treating cancer and fibrosis, including overcoming resistance to anti-cancer agents through co-administration.
Stated Advantages
Compounds tend to be selective for LDHA and/or LDHB relative to other dehydrogenases such as GAPDH and PHGDH.
Compounds exhibit desired solubility, permeability, and pharmacokinetics profiles suitable for use as anti-cancer agents.
The compounds provide improved potency, selectivity, and/or bioavailability as LDH inhibitors over previously known compounds.
Documented Applications
Treatment of cancer including various solid tumors, leukemia, melanoma, liver cancer, pancreatic cancer, lung cancer, colon cancer, brain cancer, ovarian cancer, breast cancer, prostate cancer, and renal cancer.
Treatment of fibrosis, including idiopathic pulmonary fibrosis.
Treatment of patients with cancer cells resistant to anti-cancer agents by re-sensitizing them to such agents via co-administration with the compounds.
Interested in licensing this patent?