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-9707230-B2
Publication Date
2017-07-18
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,
Core Innovation
The invention provides activators of the M2 isoform of human pyruvate kinase (PK-M2), 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), as well as compositions thereof. These compounds are useful in treating diseases that are responsive to activation of PKM2, including cancer and anemia.
Pyruvate kinase is an essential enzyme in glycolysis, with the M2 isoform expressed in fetal tissues and re-expressed in tumors, while adult tissues express other isozymes. Tumor cells down-regulate PK-M2 activity by removal of fructose-1,6-bisphosphate (FBP), leading to accumulation of glycolytic intermediates diverted for cell growth. Additionally, PK deficiency causes hemolytic anemia due to metabolic blocks in red blood cells. There is a need for new activators of PK-M2 to address these medical conditions.
Claims Coverage
The claims include three independent claims encompassing methods of treatment using specific compounds. They disclose methods of treating cancer or anemia responsive to PK-M2 activation by administering compounds of specified chemical formulas.
Methods of treating cancer or anemia using compounds of Formula (Ia′)
A method of treating cancer or anemia responsive to activation of human pyruvate kinase M2 by administering a therapeutically effective amount of compounds of Formula (Ia′), where R1 and R2 are as defined, including substituted aryl and heteroaryl groups, with specific substituents and structural features as detailed in the claim.
Methods of treating cancer or anemia using compounds of Formula (Ia″)
A method of treating cancer or anemia responsive to activation of human PKM2 by administering compounds of Formula (Ia″), where R1 and R2 are aryl or heteroaryl optionally substituted with various substituents including alkyl, haloalkyl, aryl, heterocyclyl, and others, with defined conditions for n and substituent groups.
Methods of treating cancer or anemia using compounds of Formula (Ia)
A method of treating cancer or anemia responsive to activation of human PKM2 by administering compounds of Formula (Ia), wherein R1 and R2 are phenyl optionally substituted with substituents from a broad group including alkyl, haloalkyl, aryl, heterocyclyl, and others, with conditions on n and substitution status.
The independent claims cover therapeutic methods employing specific pyruvate kinase M2 activators with defined chemical structures and substituent variations for treating cancers and anemias responsive to PKM2 activation.
Stated Advantages
The compounds show potent activation of PKM2 by increasing the enzyme's affinity for phosphoenolpyruvate (PEP) without significantly affecting ADP kinetics.
The compounds demonstrate high selectivity for the PKM2 isoform over PKM1, PKR, and PKL.
Certain compounds exhibit improved potency and efficacy compared to natural activators such as fructose-1,6-bisphosphate (FBP).
The invention provides therapeutic agents potentially effective in treating cancers and anemias associated with PKM2 activity.
Documented Applications
Treating cancer responsive to activation of human PKM2, including specific cancers such as renal cancer, ovarian cancer, breast cancer, CNS cancer, leukemia, prostate cancer, non-small cell lung cancer, colon cancer, and melanoma.
Treating anemia responsive to activation of human PKM2, specifically including hemolytic anemia such as human erythrocyte R-type pyruvate kinase deficiency.
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