Template-fixed peptidomimetics
Inventors
Obrecht, Daniel • Gombert, Frank • DeMarco, Steven J. • Ludin, Christian • Vrijbloed, Jan Wim • Moehle, Kerstin • Robinson, John-Anthony • Mukherjee, Reshmi • Henze, Heiko • Romagnoli, Barbara
Assignees
Zurich Universitaet Institut fuer Medizinische Virologie • Spexis AG
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Publication Number
US-11421001-B2
Publication Date
2022-08-23
Expiration Date
Abstract
The template-fixed β-hairpin peptidomimetics Cyclo(-Tyr-His-X-Cys-Ser-Ala-DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys-DPro-Pro), disulfide bond between Cys4 and Cys11, and pharmaceutically acceptable salts thereof, with X being Ala or Tyr, have CXCR4 antagonizing properties and can be used for where cancer is mediated or resulting from CXCR4 receptor activity.
Core Innovation
The invention relates to template-fixed β-hairpin peptidomimetics of the cyclized compound Cyclo(-Tyr-His-X-Cys-Ser-Ala-DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys-DPro-Pro) that contain a disulfide bond between Cys4 and Cys11, with X defined as Ala or Tyr. These compounds act as CXCR4 antagonists.
The disclosed compounds are presented in connection with therapeutic treatment contexts, including cancer mediated by CXCR4. The document further associates the compounds with HIV infection, including prevention and slowing progression.
Beyond CXCR4 antagonism for disease treatment, the document also describes CXCR4-dependent stem cell mobilization and hematopoietic stem cell (HSC) release, including stem cell mobilization for transplant use cases. The cyclized β-hairpin peptidomimetics are described together with pharmacological testing and safety-related assessments, including plasma stability, hemolysis, and cytotoxicity.
Claims Coverage
The provided claims include one independent claim focused on methods of treating cancer expressing CXCR4 by administering a specific Cyclo(-Tyr-His-X-Cys-Ser-Ala-DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys-DPro-Pro) compound (or a pharmaceutically acceptable salt) with a disulfide bond between Cys4 and Cys11, with X restricted to Tyr. Dependent claims further refine the method by specifying administration routes, pharmaceutical composition with an inert carrier and dosage forms, and narrowing the cancer type to breast cancer.
Treating cancer expressing CXCR4 by administering a disulfide-linked cyclized β-hairpin peptidomimetic with X=Tyr
A method for treating cancer that expresses a CXCR4 receptor by administering a therapeutically effective amount of a Cyclo(-Tyr-His-X-Cys-Ser-Ala-DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys-DPro-Pro) compound having a disulfide bond between Cys4 and Cys11 (or a pharmaceutically acceptable salt), wherein X is Tyr.
Administration route selection
The method further specifies administering the treatment via an administration route selected from oral, topical, transdermal, injection, buccal, transmucosal, pulmonary, or inhalation.
Pharmaceutically inert carrier composition and dosage forms
The method includes administering the compound as a pharmaceutical composition containing a pharmaceutically inert carrier in one of several specified dosage forms.
Breast cancer treatment
The method is carried out for breast cancer.
Overall, the claim coverage is centered on cancer treatment of subjects expressing CXCR4 by administering a therapeutically effective amount of the cyclized, disulfide-bonded β-hairpin peptidomimetic with X=Tyr, with refinements covering administration route, pharmaceutical inert carrier dosage forms, and breast cancer.
Stated Advantages
Compounds function as CXCR4 antagonists, supporting therapeutic treatment contexts including cancer mediated by CXCR4.
Associated use includes HIV infection prevention and slowing progression.
Associated use includes immunological and inflammatory disorders, including immunosuppression.
Supports CXCR4-dependent stem cell mobilization and hematopoietic stem cell (HSC) release for transplant.
Documented Applications
Treating cancer that expresses a CXCR4 receptor, including breast cancer.
HIV infection prevention and slowing progression.
Immunological and inflammatory disorders, including immunosuppression.
CXCR4-dependent stem cell mobilization and HSC release for transplant.
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