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-11247985-B2
Publication Date
2022-02-15
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 invention is directed to methods of inhibiting p97 ATPase and compounds and compositions useful in such methods. Specifically, the invention provides novel phenyl indole allosteric inhibitors of p97 and pharmaceutical compositions containing these compounds for therapeutic use. Diseases and conditions treatable with the compounds include cancer and neurodegenerative disorders susceptible to treatment by inhibition of p97.
The problem being solved is the need for effective p97 inhibitors that can treat cancers and neurodegenerative diseases caused by proteostatic malfunction. Despite p97 being a validated therapeutic target, existing p97 inhibitors showed limitations in potency or clinical efficacy. The invention addresses the need for improved p97 inhibitors with favorable biochemical activity and utility in treating conditions such as solid tumor cancers, non-small cell lung carcinoma, multiple myeloma, mantle cell lymphoma, and neurodegenerative disorders like inclusion body myopathy, Paget's disease of the bone, frontotemporal dementia, and amyotrophic lateral sclerosis.
The invention provides compounds of formula I and II, which have substituents defined by various chemical groups including alkyl, aryl, heteroaryl, and functional groups like amines, amides, sulfonamides, and halogens. These compounds exhibit p97 inhibitory activity as measured by ADP-Glo assays with IC50 values ranging from low nanomolar to low micromolar levels. Methods of treatment include administering these compounds to subjects in need of p97 inhibition to treat cancer or neurodegenerative diseases, including subjects with p97 mutations manifesting various symptoms.
Claims Coverage
The patent contains two independent claims focused on methods involving administration of compounds of formula II to subjects for p97 inhibition and treatment of non-small cell lung carcinoma.
Method of inhibiting p97 in a subject
Administering to a subject a therapeutically effective amount of a compound of formula II or a pharmaceutical composition comprising a compound of formula II and a pharmaceutically acceptable excipient to inhibit p97 ATPase activity.
Method of treating non-small cell lung carcinoma
Administering to a subject a therapeutically effective amount of a compound of formula II or a pharmaceutical composition comprising a compound of formula II and a pharmaceutically acceptable excipient to treat non-small cell lung carcinoma.
The independent claims cover methods of therapeutic treatment by administrating compounds defined by formula II to inhibit p97 and treat cancers, specifically non-small cell lung carcinoma, highlighting features such as the chemical substituents on the compound, formulation with pharmaceutically acceptable excipients, and the disease targets related to p97 inhibition.
Stated Advantages
The compounds provide potent inhibition of p97 ATPase with IC50 values in the nanomolar to low micromolar range, enabling effective modulation of p97 activity.
The invention offers a therapeutic approach targeting diseases associated with p97 including various cancers and neurodegenerative disorders, addressing unmet medical needs.
The compounds can be administered via multiple routes and formulated in different pharmaceutical compositions, offering flexibility in clinical application.
Documented Applications
Treatment of cancer, including solid tumor cancers, non-small cell lung carcinoma, multiple myeloma, and mantle cell lymphoma, by inhibition of p97.
Treatment of neurodegenerative disorders susceptible to p97 inhibition, including inclusion body myopathy (IBM), Paget's disease of the bone (PDB), frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS).
Treatment of subjects having p97 mutations with symptoms such as Parkinsonism, ataxia, cataracts, dilated cardiomyopathy, hepatic fibrosis, and hearing loss through p97 inhibition.
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