Activators of human pyruvate kinase
Inventors
Boxer, Matthew B. • Shen, Min • Auld, Douglas S. • Thomas, Craig J. • Walsh, Martin J.
Assignees
US Department of Health and Human Services
Publication Number
US-9708267-B2
Publication Date
2017-07-18
Expiration Date
2031-04-26
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Abstract
Disclosed are pyruvate kinase M2 activators which are compounds of Formula (I), including those of Formula (II), wherein A1, A2, L, R, R1 to R3, X1 to X3, k, n, and m are as defined herein, that are useful in treating a number of diseases that are treatable by the activation of PKM2, for example, cancer. A1-NR-L-A2(I).
Core Innovation
The invention provides activators of the M2 isoform of human pyruvate kinase (PKM2), including compounds of formula (I) and (II) with defined structural moieties A1, A2, L, R, R1 to R3, and substitutions as specified. These activators are useful for therapeutic purposes, particularly in treating diseases responsive to PKM2 activation, such as cancer. The compounds exhibit selective activation of PKM2 and are formulated into pharmaceutical compositions with carriers for administration.
The background identifies pyruvate kinase as a critical metabolic enzyme in glycolysis, with the M2 isoform specifically expressed in fetal tissue and re-expressed in tumors, whereas adult tissues express other isoforms. PKM2 activity is regulated by fructose-1,6-bisphosphate and can be inhibited by phosphotyrosine peptides prevalent in cancer cells, leading to metabolic changes favoring cell growth. The problem addressed is the need to identify new activators of PKM2 to modulate this pathway for therapeutic benefit.
Claims Coverage
The patent discloses 14 independent claims primarily covering novel compounds of formula (I) and (II), pharmaceutical compositions containing these compounds, and methods of treatment using these compounds.
compound of formula (I) with specific structural features
A compound of formula (I) where R is hydrogen, L is SO2 or CO, and R′ and R″ comprise specified bicyclic or phenyl-based rings with detailed substituents enabling PKM2 activation.
compound or salt variants with defined substituents
Variants of the compound where one R1 substituent includes defined groups such as halogens, alkyls, aminoalkyls, and heterocyclic moieties as detailed, affecting activity and selectivity.
compounds featuring specific R′ bicyclic rings
The R′ group includes fused bicyclic rings like 3,4-dihydroquinolin-2(1H)-onyl and related heterocycles, optionally substituted to optimize PKM2 activation.
R″ group structural variations
Defined R″ groups including phenyl, benzyl, and heteroaryl rings with optional substitutions such as halogens, alkyls, and boronic acids, contributing to functional diversity and activity.
pharmaceutical composition comprising the compounds
Formulations containing the inventive compounds or their pharmaceutically acceptable salts combined with carriers suitable for administration.
method of inhibiting tumor cell growth
Using a therapeutically effective amount of the compound or pharmaceutical composition to inhibit tumor cell growth or cell proliferation responsive to activation of human PKM2, specifically addressing various cancer types.
The claims define novel chemical entities with precise structural features that selectively activate human PKM2, pharmaceutical compositions thereof, and therapeutic methods to treat cancers and proliferative diseases by targeting PKM2 activation.
Stated Advantages
Selective activation of PKM2 without activity against other pyruvate kinase isoforms (PKL, PKM1, PKR).
Compounds demonstrate potency and efficacy in activating PKM2 with varying substituents enabling structure-activity optimization.
Pharmaceutical compositions enable diverse administration routes including oral, parenteral, topical, inhalation, and suppositories.
Compounds provide a means to inhibit tumor cell growth by targeting metabolic pathways associated with cancer proliferation via PKM2 activation.
Documented Applications
Treatment or prevention of cancer by administering PKM2 activators.
Use in diseases responsive to PKM2 activation including obesity, type II diabetes, atherosclerosis, restenosis, autoimmune diseases, and proliferation-dependent diseases.
Specific application in treating a wide variety of cancers including leukemias, lymphomas, sarcomas, carcinomas, and other solid tumors.
Use in modulating adipose tissue metabolism to reduce adiposity contributing to type II diabetes.
Therapeutic application in autoimmune disorders such as type I diabetes, multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, and others.
Use in proliferative diseases like benign prostatic hyperplasia, psoriasis, lymphoproliferative disorders, chronic rheumatoid arthritis, arteriosclerosis, restenosis, and diabetic retinopathy.
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