Non-immunosuppressive FK506 analogs and use thereof
Inventors
Liu, Jun O. • Sun, Zhaoli • Peiffer, Brandon J. • Wang, Yuefan • Qi, Le • Guo, Zufeng • Peng, Hanjing • Ahmadi, Ali
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Assignees
MemberJohns Hopkins UniversityJohns Hopkins UniversityFounded in 1876, Johns Hopkins University is recognized as the first research university in the United States. It advances interdisciplinary education, high-impact research, and global outreach, supporting knowledge translation, technological innovation, and community partnerships. The university fosters academic excellence, innovation incubation, outreach, and inclusion across multiple campuses in Baltimore, integrating into the city's social, economic, and cultural life.
Founded in 1876, Johns Hopkins University is recognized as the first research university in the United States. It advances interdisciplinary education, high-impact research, and global outreach, supporting knowledge translation, technological innovation, and community partnerships. The university fosters academic excellence, innovation incubation, outreach, and inclusion across multiple campuses in Baltimore, integrating into the city's social, economic, and cultural life.
Publication Number
US-12662493-B2
Publication Date
2026-06-23
Expiration Date
Abstract
The present invention provides a new class of non-immunosupressive FK506 analogs which are FRBP-selective, small-molecule BMP agonists with modest potency therepeutics for tissue repair and regeneration. Also disclosed herein are methods for making and use of these compounds.
Core Innovation
The invention relates to non-immunosuppressive compounds of formula I, including salts, solvates, isomers, and pharmaceutically acceptable derivatives thereof. The disclosure focuses on non-immunosuppressive FK506 (tacrolimus) derivatives that bind FKBP12 but lack calcineurin inhibition, and on their use in pharmaceutical compositions for tissue injury treatments, including wound healing and modulating the wound healing response.
The invention further covers pharmaceutical compositions comprising a non-immunosuppressive compound of formula I with a pharmaceutically acceptable carrier, optionally including at least one stem cell mobilizer and/or at least one additional biologically active agent. The biological rationale connects these compounds to BMP receptor-related signaling, including BMP type 1 receptor/SMAD1/5 and ID-1 activation without SMAD2/3, and describes FKBP12 dependence interplay with mTOR/calcineurin.
The disclosure also supports aryl-substituted FK506 analogs through a Heck-reaction-based synthetic approach at the terminal alkenyl position to introduce aryl substituents, and includes structural characterization for representative compounds such as FKVP. Experimental support is described for structure-dependent immunosuppressive profiles and accelerated wound healing in diabetic rats using combinations including AMD3100 with FK506 analogs.
Claims Coverage
The provided independent claims cover three core subject matters: non-immunosuppressive compounds of formula I, pharmaceutical compositions comprising such compounds with a pharmaceutically acceptable carrier, and compositions comprising such compounds with at least one stem cell mobilizer. Across these independent claims, the inventive features center on the non-immunosuppressive formula I definition, inclusion in a pharmaceutical composition, and association with stem cell mobilization.
Non-immunosuppressive compound of formula I variants
A non-immunosuppressive compound of formula I, or a salt, solvate, or isomer thereof, wherein R is selected from the stated options.
Composition comprising non-immunosuppressive compound of formula I
A composition comprising a non-immunosuppressive compound of formula I, or a salt, solvate, or isomer thereof, together with an additional biologically active agent.
Stem cell mobilizer composition with pharmaceutically acceptable carrier
A composition comprising a non-immunosuppressive compound of formula I, or a salt, solvate, or isomer thereof, at least one stem cell mobilizer, and a pharmaceutically acceptable carrier.
Overall, the claim coverage is anchored on non-immunosuppressive compounds of formula I, their incorporation into pharmaceutical compositions, and their association with stem cell mobilization.
Stated Advantages
BMP agonist activity through FRBP-selective small-molecule action while lacking calcineurin inhibition associated with immunosuppressive effects.
Accelerates wound healing in diabetic rats in a BMP receptor-dependent manner when combined with the CXCR4 antagonist stem cell mobilizer AMD3100.
Accelerates wound healing in diabetic GK rats using combinations including AMD3100 with FK506 analogs.
A structure-dependent immunosuppressive profile for FK506 analogs, including BMP type 1 receptor/SMAD1/5 and ID-1 activation without SMAD2/3.
BMP/NFAT and related signaling effects consistent with the non-immunosuppressive profile, including FKBP12 dependence and binding interplay with mTOR/calcineurin.
Eliminates calcineurin immunosuppression via FKVP.
Supports intestinal mucosal regeneration.
Accelerates wound healing.
Documented Applications
Wound healing and modulating the wound healing response in tissue injury contexts.
Use in connection with transplant acceptance [procedural detail omitted for safety].
Treatment of inflammatory/autoimmune disorders, including inflammatory bowel disease (IBD) [procedural detail omitted for safety].
Wound healing in diabetic rats, where combination with the CXCR4 antagonist stem cell mobilizer AMD3100 accelerates wound healing in a BMP receptor-dependent manner.
Tissue injury treatment using formula I compounds in combination with stem cell mobilizers and additional biologically active agents.
Accelerated wound healing in diabetic GK rats using combinations including AMD3100 with FK506 analogs.
Treatment or supportive use for full-thickness excisional wound healing.
Support of intestinal mucosal regeneration, including context related to inflammatory bowel disease (IBD).
Support of organ transplant acceptance.
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