ArticleACS combinatorial science2011
Creating diverse target-binding surfaces on FKBP12: synthesis and evaluation of a rapamycin analogue library.
Article in ACS combinatorial science, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed.
- Beyond natural targets: chemical synthesis reprograms the target specificity of rapamycin.National science review · 2022Article
- Recent Advances in Macrocyclic Drugs and Microwave-Assisted and/or Solid-Supported Synthesis of Macrocycles.Molecules (Basel, Switzerland) · 2022Review
- A Curvilinear-Path Umbrella Sampling Approach to Characterizing the Interactions Between Rapamycin and Three FKBP12 Variants.Frontiers in molecular biosciences · 2022Article
- Hemiacetal-less rapamycin derivatives designed and produced by genetic engineering of a type I polyketide synthase.Scientific reports · 2021Article
- The design and development of covalent protein-protein interaction inhibitors for cancer treatment.Journal of hematology & oncology · 2020Review
- Rapamycin-inspired macrocycles with new target specificity.Nature chemistry · 2019Article
- Synthesis and biological evaluation of rapamycin-derived, next generation small molecules.MedChemComm · 2018Review
- BMP type II receptor as a therapeutic target in pulmonary arterial hypertension.Cellular and molecular life sciences : CMLS · 2017Review
- Recent development of ATP-competitive small molecule phosphatidylinostitol-3-kinase inhibitors as anticancer agents.Oncotarget · 2017Review
- Quantum mechanics implementation in drug-design workflows: does it really help?Drug design, development and therapy · 2017Review
- FK506 activates BMPR2, rescues endothelial dysfunction, and reverses pulmonary hypertension.The Journal of clinical investigation · 2013Article
- Inhibition of Ras-Effector Interaction by Cyclic Peptides.MedChemComm · 2013Article
Corrections and comments
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Authors and funding
9 authors.
Funding
Abstract
FK506 and rapamycin are immunosuppressive drugs with a unique mode of action. Prior to binding to their protein targets, these drugs form a complex with an endogenous chaperone FK506-binding protein 12 (FKBP12). The resulting composite FK506-FKBP and rapamycin-FKBP binding surfaces recognize the relatively flat target surfaces of calcineurin and mTOR, respectively, with high affinity and specificity. To test whether this mode of action may be generalized to inhibit other protein targets, especially those that are challenging to inhibit by conventional small molecules, we have developed a parallel synthesis method to generate a 200-member library of bifunctional cyclic peptides as FK506 and rapamycin analogues, which were referred to as "rapalogs". Each rapalog consists of a common FKBP-binding moiety and a variable effector domain. The rapalogs were tested for binding to FKBP12 by a fluorescence polarization competition assay. Our results show that FKBP12 binds to most of the rapalogs with high affinity (K(I) values in the nanomolar to low micromolar range), creating a large repertoire of composite surfaces for potential recognition of macromolecular targets such as proteins.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.