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-10351532-B2
Publication Date
2019-07-16
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) that effectively inhibit lactate dehydrogenase A (LDHA) and/or lactate dehydrogenase B (LDHB) activity. These compounds are capable of treating cancer and fibrosis, including idiopathic pulmonary fibrosis, by selectively targeting LDHA and/or LDHB relative to other dehydrogenases such as GAPDH and PHGDH. The compounds may also have desirable solubility, permeability, and pharmacokinetic profiles suitable for anti-cancer therapeutics.
The background identifies the problem that existing LDHA inhibitors, such as gossypol and derivatives of quinoline compounds, suffer from nonselectivity or poor in vivo bioavailability. Cancer tissues rely heavily on aerobic glycolysis through the Warburg effect, with increased LDH activity being essential for tumor survival and growth. There remains a need to provide novel LDH inhibitors with improved potency, selectivity, and bioavailability for cancer treatment.
Claims Coverage
The patent claims cover one independent compound claim and multiple dependent claims focusing on structural and functional features of the compounds of formula (Ia) and (Ib).
Compound of formula (Ia) and its specific substituents
Claim 1 defines a compound of formula (Ia) with specified features including R1 being hydroxyl, halo, —CO2H, —SO2NH2, C1-C4alkyl, C1-C4alkoxy, etc.; R2 chosen from F and —SO2NH2 with one R2 being —SO2NH2; and R3 selected from halogen, hydroxyl, SF5, various hydrocarbyls, and substituted heteroaryl groups as detailed.
Selective substituent features for the compound of formula (Ia)
Claims 3-6 further specify features such as R2 being —SO2NR5R6 with R5 and R6 being H or C1-C8 alkyl, n being 1, R3 independently being halo, haloalkyl, haloalkoxy, alkyl, alkenyl, alkynyl, or phenyl, m being 1 or 2, X1 as —CH2— and X2 as —S, and only one of Y1-Y5 being N.
Specific compound sub-formulas and substituent definitions
Claims 7-13 define compounds of formula (Ia-1) through (Ia-4), detailing substituent options for Ra, R2, R3, R10, and others, including heteroaryl and alkyl substitutions, cycloalkyl groups, and further specifying substitution patterns and ring systems.
Compound of formula (Ib) and specific substituents
Claim 14 and its dependents define compounds of formula (Ib) where R1 is —CO2H or —CO2(C1-C8 alkyl), R2 is —SO2NR5R6 with R5 and R6 being H or C1-C8 alkyl, n is 1, R3 includes halo and other hydrocarbon groups, m is 0-2, and R10 includes alkyl, cyclopropyl, phenyl, benzyl, and other substituents; with X1 and X2 defined as —CR8R9—, —O—, —NH—, or —S—.
Pharmaceutical and therapeutic claims
Claims 19-21 cover pharmaceutical compositions comprising at least one compound or prodrug or pharmaceutically acceptable salt thereof and methods of treatment of fibrosis, cancer, and anti-cancer resistant cells by administering effective amounts of such compounds, alone or in combination with anti-cancer agents, to sensitize cancer cells.
The claims encompass a broad class of small molecule compounds characterized by detailed structural elements and substituents designed to inhibit LDHA and LDHB selectively. They also include compositions and methods for treating cancer and fibrosis using these compounds, emphasizing selectivity, potency, and re-sensitization of resistant cancer cells.
Stated Advantages
Compounds exhibit selectivity for LDHA and/or LDHB relative to other dehydrogenases such as GAPDH and PHGDH.
Compounds possess desired solubility, permeability, and pharmacokinetic profiles suitable for anti-cancer agents.
Inhibition of LDHA and/or LDHB reduces tumor cell proliferation and tumor growth and stimulates mitochondrial respiration as a compensatory mechanism.
Compounds can re-sensitize cancer cells to anti-cancer agents, potentially overcoming resistance.
Documented Applications
Treatment of cancer, including solid tumors and various cancer types 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, including combination therapy with such agents to re-sensitize cancer cells.
Inhibition of LDHA and/or LDHB enzymatic activity in cells.
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