Inhibitors of the peptidyl-prolyl cis/trans isomerase (PIN1), combinations and uses thereof
Inventors
KE, Shizhong • Wulf, Gerburg • Zhou, Xiao Zhen • LONDON, Nir • Wei, Wenyi • Lu, Kun Ping • Gray, Nathanael S. • Nabet, Behnam
Assignees
Yeda Research and Development Co Ltd • Dana Farber Cancer Institute Inc • Beth Israel Deaconess Medical Center
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Publication Number
US-12728132-B2
Publication Date
2026-09-08
Expiration Date
Abstract
Disclosed are methods of treating diseases or disorders mediated by dysregulated CDK4/6 and/or Pin 1 activity comprising co-administering a therapeutically effective amount of one or more CDK4/6 inhibitors, and a therapeutically effective amount of one or more Pin1 inhibitors, or a pharmaceutically acceptable salt or salts thereof.
Core Innovation
The disclosure provides methods and compositions for treating diseases or disorders mediated by dysregulated cyclin-dependent kinase 4/6 (CDK4/6) activity or reducing CDK4/6 activity in a cell. The approach co-administers one or more CDK4/6 inhibitors and one or more peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (Pin1) inhibitors, or pharmaceutically acceptable salts thereof. Pharmaceutical compositions and kits comprise specific CDK4/6 inhibitors, including palbociclib, abemaciclib, or ribociclib, combined with Pin1 inhibitors such as sulfopin, ATRA, or ATO.
Mechanistically, CDK4-mediated phosphorylation and Pin1 isomerization inhibit APC/C-Cdh1, whereas combined inhibition restores APC/C-Cdh1 activity, promotes Pin1 ubiquitination and degradation, and induces cell-cycle arrest. In preclinical breast cancer models, including triple-negative and endocrine-resistant estrogen receptor-positive forms, these combinations suppress tumor growth, alter immune-cell populations, and improve survival alone or with immunotherapy.
Claims Coverage
The independent claims define two inventive features directed to a treatment method and a pharmaceutical composition.
Co-administration of CDK4/6 and Pin1 inhibitors
The claim covers co-administering therapeutically effective amounts of one or more CDK4/6 inhibitors and one or more Pin1 inhibitors, or pharmaceutically acceptable salts thereof, to treat a disease or disorder mediated by dysregulated CDK4/6 activity in a subject, or to reduce CDK4/6 activity in a cell, in vivo or in vitro.
Pharmaceutical composition comprising specified inhibitors
The claim covers a pharmaceutical composition comprising therapeutically effective amounts of one or more CDK4/6 inhibitors selected from palbociclib, abemaciclib, ribociclib, or combinations thereof, and one or more Pin1 inhibitors selected from sulfopin, ATRA, ATO, or combinations thereof, or pharmaceutically acceptable salts or stereoisomers thereof.
The independent claims cover the co-administration of CDK4/6 and Pin1 inhibitors for treatment or reduction of cellular CDK4/6 activity, as well as pharmaceutical compositions comprising specified CDK4/6 and Pin1 inhibitors.
Stated Advantages
A greater therapeutic effect from co-administration compared to CDK4/6 inhibitor monotherapy without Pin1 inhibitors, including synergistic antitumor effects or reduced tumor growth in triple-negative breast cancer.
Enhanced tumor-growth suppression and improved survival in BT3 mouse tumor models.
Immune activation and improved survival in combination with checkpoint blockade.
Limited toxicity reported in preclinical models.
Documented Applications
Treatment of diseases or disorders mediated by dysregulated CDK4/6 activity, including cancer.
Treatment of triple-negative breast cancer and endocrine-resistant ER-positive breast cancer in local, locally advanced, or metastatic forms.
Reduction of CDK4/6 activity in a cell, either in vivo or in vitro.
Combination therapy with anti-PD-1 or anti-PD-L1 immunotherapy.
Pharmaceutical compositions and kits containing CDK4/6 and Pin1 inhibitors for administration to a subject or contacting a biological sample.
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