Phenyl indole allosteric inhibitors of p97 ATPase
Inventors
Huryn, Donna M. • Wipf, Peter • Laporte, Matthew G. • Colombo, Raffaele • Kovaliov, Marina • LIM, Chaemin • Alverez, Celeste Natalie • Yue, Zhizhou • Samankumara, Lalith Palitha • Chatterley, Alexander Julian • Yan, Yongzhao • LIANG, Mary • Green, Neal J. • Baldwin, Eric T. • Moore, William J. • Arkin, Michelle • Neitz, R. Jeffrey • Ang, Kean-Hooi • Bryant, Clifford • Bulfer, Stacie
Assignees
University of Pittsburgh • National Institutes of Health NIH • University of California San Diego UCSD • Government of the United States of America
Publication Number
US-10633370-B2
Publication Date
2020-04-28
Expiration Date
2036-10-20
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Abstract
The present invention is directed to methods of inhibiting p97 and compounds and compositions useful in such methods. Diseases and conditions the can be treated with the compounds and compositions of the invention include, but are not limited to, cancer and neurodegenerative disorders susceptible to treatment by inhibition of p97.
Core Innovation
The present invention is directed to methods of inhibiting p97 and compounds and compositions useful in such methods. The compounds have a core structure defined by formula (I) or formula (II), with detailed substituent variables that include alkyl, aryl, heteroaryl, and other functional groups. These compounds can be administered alone or in pharmaceutical compositions to subjects in need.
p97 is a AAA ATPase involved in diverse cellular functions including autophagy, endosomal sorting, protein degradation at the mitochondrial membrane, and chromatin-associated processes. Dysfunction or mutation in p97 is associated with diseases such as inclusion body myopathy, Paget's disease of the bone, frontotemporal dementia, and amyotrophic lateral sclerosis, as well as various cancers.
There is a recognized need for effective p97 inhibitors to treat cancers and neurodegenerative disorders that are susceptible to p97 inhibition. Prior art includes various small molecule inhibitors, but there remains an unmet need for novel compounds with improved efficacy and selectivity. The invention provides a class of phenyl indole allosteric inhibitors that address this need.
Claims Coverage
The patent includes two independent claims covering compounds with a defined chemical structure and methods of inhibiting p97 and treating diseases by administering these compounds or compositions containing them. There are 2 main inventive features extracted from these claims.
Compounds with a specific phenyl indole structure and substituents for p97 inhibition
The invention claims compounds of formula (I) and (II) characterized by a phenyl indole core with detailed substituents such as R1, R2, R3, L1, X, Y, L2, and A where each can be hydrogen, halogen, cyano, alkyl, aryl, heteroaryl or other specified functional groups. These compounds exclude certain prior art structures and include pharmaceutically acceptable salts.
Methods of inhibiting p97 and treating cancer and neurodegenerative disorders by administering these compounds
The invention claims methods of inhibiting p97 in subjects by administering therapeutically effective amounts of the compounds of formula (I) or (II) or pharmaceutical compositions thereof. Also claimed are methods of treating cancers and neurodegenerative disorders susceptible to p97 inhibition using these compounds or compositions, including diseases such as solid tumors, non-small cell lung carcinoma, multiple myeloma, mantle cell lymphoma, inclusion body myopathy, Paget's disease of bone, frontotemporal dementia, and amyotrophic lateral sclerosis.
The claims cover novel phenyl indole compounds with defined substituent patterns and their use in inhibiting p97. The scope extends to pharmaceutical compositions and methods of treating cancers and neurodegenerative diseases by administering these compounds.
Stated Advantages
The compounds effectively inhibit p97 ATPase activity at low micromolar to nanomolar concentrations as demonstrated by ADP-Glo assay IC50 values, showing significant potency.
The compounds have potential therapeutic benefit in treating cancers and neurodegenerative disorders associated with p97 malfunction.
The compounds can be formulated in various pharmaceutical compositions suitable for different administration routes including oral and intravenous.
Combination therapy with proteasome inhibitors, heat shock protein inhibitors, or other anti-cancer agents is possible, potentially enhancing therapeutic efficacy.
Documented Applications
Treatment of cancers such as solid tumors, non-small cell lung carcinoma, multiple myeloma, and mantle cell lymphoma through p97 inhibition.
Treatment of neurodegenerative disorders including inclusion body myopathy, Paget's disease of the bone, frontotemporal dementia, and amyotrophic lateral sclerosis by inhibiting p97.
Treatment of subjects having p97 mutations manifesting symptoms like Parkinsonism, ataxia, cataracts, dilated cardiomyopathy, hepatic fibrosis, and hearing loss.
Use of the compounds in pharmaceutical compositions for administration via oral, intravenous, topical, intranasal, intramuscular, subcutaneous, transdermal, intracerebroventricular, or intrathecal routes.
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