Activators of the human pyruvate kinase M2 receptor
Inventors
Thomas, Craig J. • Auld, Douglas S. • Inglese, James • Skoumbourdis, Amanda P. • Jiang, Jian-Kang • Boxer, Matthew B.
Assignees
US Department of Health and Human Services
Publication Number
US-8841305-B2
Publication Date
2014-09-23
Expiration Date
2029-10-09
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Abstract
Disclosed are pyruvate kinase M2 activators, which are bis sulfonamide piperazinyl and piperidinyl compounds of Formula (I), 2,4-disubstituted 4H-thieno[3,2-c]pyrrole-2-(substituted benzyl)pyridazin-3(2H)-ones of Formula (II) and 6-(3,4-dimethylphenylaminosulfonyl)-3,4-dihydro-1H-quinolin-2-one of formula (III), wherein L, R1, R2, R11 to R16, R21 and R22 are as defined herein, that are useful in treating a number of diseases that are treatable by the activation of PKM2, for example, cancer and anemia.
Core Innovation
The invention provides novel activators of the M2 isoform of human pyruvate kinase (PKM2). These activators include bis sulfonamide piperazinyl and piperidinyl compounds of Formula (I), 2,4-disubstituted 4H-thieno[3,2-c]pyrrole-2-(substituted benzyl)pyridazin-3(2H)-ones of Formula (II), and 6-(3,4-dimethylphenylaminosulfonyl)-3,4-dihydro-1H-quinolin-2-one of formula (III). The compounds are designed as therapeutic agents that activate PKM2, which is re-expressed in tumors and fetal tissues but absent in most adult tissue, thereby providing a means to treat diseases responsive to PKM2 activation such as cancer and anemia.
The problem addressed by the invention is the need for novel activators of PKM2 due to its role in cancer metabolism and certain forms of anemia. Specifically, tumor cells exhibit a metabolic transformation involving the expression of PKM2 isoform, which has low affinity for phosphoenolpyruvate (PEP) and can be allosterically regulated, resulting in diversion of glycolytic intermediates towards biosynthesis necessary for cell proliferation. Moreover, PK deficiency causes hemolytic anemia, and activation of PKM2 may compensate for deficient isoforms in red blood cells. Existing activators like fructose-1,6-bisphosphate (FBP) regulate PKM2, but novel compounds with selective activation and utility are desired.
Claims Coverage
The patent contains three independent claims directed to compounds of formula (Ia'), formula (Ia''), and pharmaceutical compositions thereof. These claims define key inventive chemical features and therapeutic utilities of the compounds.
Compounds of formula (Ia') and related structures
The invention claims compounds characterized by having R1 and R2 as aryl or heteroaryl groups optionally substituted with a wide variety of substituents and linked by a linker L comprising an amino group, wherein R1 and R2 are not simultaneously dimethoxyphenyl or both 4-methylphenyl. These compounds include specific substitutions detailed in the patent that yield potent and selective activators of PKM2.
Compounds of formula (Ia'') and pharmaceutical acceptable salts thereof
This feature covers specific compounds within formula (Ia'') that have R1 and R2 as aryl, phenyl, or heteroaryl groups optionally substituted with various functional groups, including alkyl, haloalkyl, cycloalkyl, heteroaryl, among others, and with additional structural features such as R3 to R10 substituents and X being CH or N. It also includes pharmaceutically acceptable salts of these compounds.
Pharmaceutical compositions comprising the compounds
Pharmaceutical compositions comprising the inventive compounds or salts thereof with pharmaceutically acceptable carriers are claimed. These compositions are intended for therapeutic administration and encompass various formulations suitable for diseases responsive to PKM2 activation, such as cancer and anemia.
The independent claims cover novel chemical entities characterized by specific aryl or heteroaryl sulfonamide substitutions and linkers for selective activation of human PKM2, pharmaceutical compositions of these compounds, and methods of treating PKM2-responsive diseases, emphasizing chemical structures, substituent patterns, and pharmaceutical formulations.
Stated Advantages
The activators increase the affinity of PKM2 for phosphoenolpyruvate (PEP) without significantly affecting the affinity for ADP, thereby mimicking the activated state of PKM2.
The compounds demonstrate selectivity for activating PKM2 over other pyruvate kinase isoforms PKM1, PKR, and PKL.
The activators show efficacy in enhancing enzymatic activity and have potential therapeutic utility in treating cancer and anemia by modulating PKM2 activity.
Documented Applications
The compounds are explicitly described as useful in treating diseases responsive to PKM2 activation, including various cancers such as renal cancer, ovarian cancer, breast cancer, central nervous system cancer, leukemia, prostate cancer, non-small cell lung cancer, colon cancer, and melanoma.
The compounds are also useful in treating forms of anemia associated with pyruvate kinase deficiency, specifically human erythrocyte R-type pyruvate kinase deficiency and hemolytic anemia.
Interested in licensing this patent?