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-10961200-B2
Publication Date
2021-03-30
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
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. While normal tissue typically uses glycolysis only when the oxygen supply is low, cancer tissue relies heavily on aerobic glycolysis regardless of the oxygen supply level. This property is known as the Warburg effect. Lactate dehydrogenase (LDH) is involved in the final step of glycolysis, converting pyruvate to lactate. The increased lactate production and decreased pyruvate entry into the TCA cycle are vital for tumor growth and survival. LDHA and LDHB are subunits of LDH that catalyze this process. Elevated serum total LDH5, a tetramer of LDHA, and up-regulation of the LDHA gene are frequently observed in cancer patients. Inhibiting LDH is expected to reduce tumor cell proliferation and growth by limiting effective glucose metabolism.
Prior LDHA inhibitors, such as gossypol and derivatives of certain benzoic acids, have shown activity but were limited by poor in vivo bioavailability or selectivity. Therefore, there remains a need for novel LDH inhibitors with improved potency, selectivity, and/or bioavailability for cancer treatment.
The present invention provides compounds of formula (I) that inhibit LDHA and/or LDHB activity and are effective in treating cancer. Such compounds tend to be selective for LDHA and/or LDHB relative to other dehydrogenases and exhibit desirable solubility, permeability, and pharmacokinetics suitable for anti-cancer agents. They can also be used to treat fibrosis, including idiopathic pulmonary fibrosis.
Methods are provided for treating cancer or fibrosis by administering compounds of formula (I) or their prodrugs or pharmaceutically acceptable salts. Additionally, co-administration of these compounds with other anti-cancer agents can re-sensitize resistant cancer cells. The compounds inhibit LDHA and/or LDHB activity in cells, measurable by enzymatic assays.
Claims Coverage
The patent discloses 18 inventive features extracted from the independent claims, focusing on a compound or salt of formula (Ib) and its structural and functional characteristics, pharmaceutical compositions containing it, and methods of treatment.
Compound or salt of formula (Ib)
A compound or salt of formula (Ib) defined by specific chemical structure with substituents R1, R2, R3, R5, R6, R10, X1, X2, and X3 and indices m, n, p.
Defined substituents for R10
R10 can be hydrogen, substituted or unsubstituted C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C6 cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, hydroxyl, hydroxyalkyl, halo, haloalkyl, cyano groups, NR5R6, or heteroarylalkyl.
Further limitation on R10
R10 can more specifically be substituted or unsubstituted C1-C3 alkyl, cyclopropyl, cyclopropylalkyl, vinyl, alkynyl cyclopropyl, phenyl, benzyl, hydroxyl, hydroxymethyl, trifluoromethyl, difluoroethyl, halogens, cyano, aminomethyl, or tetrazolylmethane.
Specific forms of R1
R1 is —CO2H or —CO2(C1-C8 alkyl) substituted or unsubstituted.
Specific forms of R5 and R6
R5 and R6 may be independently hydrogen or C1-C8 alkyl.
Specific forms of R3 substituents
Each R3 independently may be halo, haloalkyl, haloalkoxy, substituted or unsubstituted alkyl, alkenyl, alkynyl, or substituted or unsubstituted methylene-substituted aryl, heteroaryl, or heterocycloalkyl.
Value of m in formula (Ib)
m is 0, 1, or 2.
Possible values of X1
X1 may be —CR8R9—, —O—, or —NH—, with specifics favoring —CH2—.
Specific substitution for X1
X1 is preferably —CH2—.
Specific substitution for X2
X2 is preferably —S—.
Character of X3
X3 is CH.
Representative structural forms
Specific exemplary chemical structures falling within formula (Ib) are disclosed as preferred embodiments.
Specified substituents composition
Substituents R1, R2, R3, and R10, along with X1, X2, m, n, and p, are defined with specific chemical substitutions and integer ranges as per formula.
Pharmaceutical composition
Pharmaceutical compositions comprising a compound or pharmaceutically acceptable salt of formula (Ib) and a pharmaceutically acceptable carrier.
Pharmaceutical composition with specific compound
Pharmaceutical composition comprising the compound as claimed in a preferred formula and carrier.
Method for treating fibrosis or cancer
A method of treating fibrosis or cancer by administering an effective amount of a compound or pharmaceutically acceptable salt of formula (Ib).
Method for treating fibrosis or cancer with specific compound
Treatment of fibrosis or cancer with an effective amount of the compound of a specified formula or pharmaceutically acceptable salt thereof.
The claims cover small molecule compounds of formula (Ib) structurally characterized by selective substituents that inhibit LDHA and/or LDHB, their pharmaceutical compositions, and methods of treatment for fibrosis and cancer.
Stated Advantages
The compounds tend to be selective for LDHA and/or LDHB relative to other dehydrogenases.
They have desirable solubility, permeability, and pharmacokinetics (ADME) suitable for anti-cancer agents.
Inhibition of LDH is expected to reduce tumor cell proliferation and tumor growth.
The inhibitors can re-sensitize cancer cells resistant to anti-cancer agents.
Documented Applications
Treatment of cancer including types with increased aerobic glycolysis (Warburg effect) by inhibiting LDHA and/or LDHB.
Treatment of fibrosis including idiopathic pulmonary fibrosis.
Treatment of patients with cancer cells resistant to anti-cancer agents by administering the compounds alone or with other anti-cancer agents or radiation therapy, to resensitize the cancer cells.
Inhibition of lactate dehydrogenase enzyme activity in cells.
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