Activators of human pyruvate kinase
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-9290512-B2
Publication Date
2016-03-22
Expiration Date
2029-10-09
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Abstract
Disclosed are pyruvate kinase M2 activators, which are, bis sulfonamide piperazinyl compounds of Formula (I) and 2,4-disubstituted 4H-thieno[3,2-b]pyrrole-2-(substituted benzyl)pyridazin-3(2H)ones of Formula (II), wherein L and R1 to R16 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, Formulas (I); (II).
Core Innovation
The invention provides pyruvate kinase M2 (PKM2) activators comprising bis sulfonamide piperazinyl compounds of Formula (I) and 2,4-disubstituted 4H-thieno[3,2-b]pyrrole-2-(substituted benzyl)pyridazin-3(2H)ones of Formula (II), characterized by various substituents and linkers as defined in the patent. These compounds are used in pharmaceutical compositions and methods for activating PKM2, with therapeutic applications in treating diseases that respond to PKM2 activation, such as cancer and anemia.
The problem addressed is that PKM2, an isozyme re-expressed in tumors and fetal tissues, undergoes downregulation in cancer and certain anemias due to interaction with phosphotyrosine peptides and genetic deficiencies. This downregulation alters metabolism crucial for cell growth and red blood cell survival. Existing therapies lacked new activators for PKM2, creating a need for selective activators with suitable pharmaceutical properties.
The invention solves this problem by providing novel chemical compounds that activate PKM2 allosterically, increasing its affinity for phosphoenolpyruvate without significantly affecting ADP kinetics. These compounds restore or enhance PKM2 enzymatic activity, countering metabolic blocks in cancer cells and red blood cells with PK deficiency. The invention includes detailed chemical structures, synthetic methods, and pharmaceutical formulations, enabling their use as therapeutic agents.
Claims Coverage
The patent contains one independent method claim covering the treatment of diseases responsive to activation of human PKM2 by administering compounds of Formula II. The claims specify various substituent patterns and disease targets.
Method of treating disease responsive to PKM2 activation
A method comprising administering to a patient a therapeutically effective amount of a compound of Formula II that activates human pyruvate kinase M2.
Compounds with defined substituents for therapeutic use
The compounds have substituents R11 to R16 selected from specific chemical groups including alkyl, halogen, alkoxy, nitro, cyano, and others with particular provisos on substitution patterns, enabling selective activation of PKM2.
Treatment of specific cancers and anemia
The method is directed to treatment of cancers including non-small cell lung cancer and leukemia, as well as hemolytic anemia, through PKM2 activation by the compounds.
The claims focus on therapeutic methods using specified compounds of Formula II characterized by precise structural substituents for selective activation of human PKM2, addressing treatments of cancer and anemia through enzymatic activation.
Stated Advantages
Compounds selectively activate PKM2, increasing its affinity for phosphoenolpyruvate, thereby restoring enzymatic function.
High selectivity of compounds for PKM2 over PKM1, PKL, and PKR isoforms reduces off-target effects.
The activators can be formulated in various pharmaceutical compositions suitable for multiple routes of administration.
The compounds help reverse metabolic blocks associated with cancer metabolism and anemia caused by PK deficiency.
Documented Applications
Treatment or prevention of cancers responsive to PKM2 activation, including renal, ovarian, breast, CNS cancers, leukemia, prostate cancer, non-small cell lung cancer, colon cancer, and melanoma.
Treatment of anemia, specifically hemolytic anemia associated with human erythrocyte R-type pyruvate kinase deficiency.
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