Degradation of rapamycin and its ring-opened isomer: Role of base catalysis

Il’ichev, Yuri V.; Alquier, Lori; Maryanoff, Cynthia A.

doi:10.3998/ark.5550190.0008.c09

Cited by 25 publications

(9 citation statements)

References 22 publications

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“…Comparable seco-species are a well-known degradant from rapamycin itself (where it is known as secorapamycin 34), which forms in vivo, 91,92 under enzymatic processes (CYP 3A4) 89,90 and under basic conditions. 72,74,75 Testing of the seco-products 32 and 33, formed from bi-steric inhibitors 16 and 30, respectively, indicated that they were much less potent as mTORC1 or mTORC2 inhibitors (Table 4). Due to the prevalence of a seco-product when bi-steric inhibitors containing a C32 carbonyl were dosed to rodents or when subjected to mildly basic conditions (Scheme 3), we sought to prepare additional compounds that would be less susceptible to forming a ring-opened degradant.…”

Section: ■ Chemistrymentioning

confidence: 99%

Discovery of RMC-5552, a Selective Bi-Steric Inhibitor of mTORC1, for the Treatment of mTORC1-Activated Tumors

et al. 2022

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Hyperactivation of mTOR kinase by mutations in the PI3K/mTOR pathway or by crosstalk with other mutant cancer drivers, such as RAS, is a feature of many tumors. Multiple allosteric inhibitors of mTORC1 and orthosteric dual inhibitors of mTORC1 and mTORC2 have been developed as anticancer drugs, but their clinical utility has been limited. To address these limitations, we have developed a novel class of “bi-steric inhibitors” that interact with both the orthosteric and the allosteric binding sites in order to deepen the inhibition of mTORC1 while also preserving selectivity for mTORC1 over mTORC2. In this report, we describe the discovery and preclinical profile of the development candidate RMC-5552 and the in vivo preclinical tool compound RMC-6272. We also present evidence that selective inhibition of mTORC1 in combination with covalent inhibition of KRASG12C shows increased antitumor activity in a preclinical model of KRAS G12C mutant NSCLC that exhibits resistance to KRASG12C inhibitor monotherapy.

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Section: ■ Chemistrymentioning

confidence: 99%

Discovery of RMC-5552, a Selective Bi-Steric Inhibitor of mTORC1, for the Treatment of mTORC1-Activated Tumors

et al. 2022

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“…Values of observed rate constants(k obs ) of tacrolimus in HPβCD solution at pH 5 and 9 with and without 0.1% EDTA. compounds, like everolimus and sirolimus, where the lactone group is hydrolyzed as explained byIl'ichev et al (Il'ichev et al, 2007) (Nogueiras-Nieto, 2012. Another less polar compound was obtained at 4.38 RT with m/z 808.…”

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confidence: 99%

Stability characterization, kinetics and mechanism of tacrolimus degradation in cyclodextrin solutions

Prajapati

Eiríksson²,

Loftsson

2020

International Journal of Pharmaceutics

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Tacrolimus is a macrolide lactone and potent immunosuppressant. It is highly lipophilic and has very limited aqueous solubility. Tacrolimus is highly susceptible to hydrolysis which results in very limited stability in aqueous solutions. Besides this, tacrolimus also undergoes dehydration and epimerization. Cyclodextrin (CD) complexation can increase the solubility and stability of hydrophobic drugs in aqueous solutions through the formation of drug/CD complexes. The aim of this study was to investigate degradation kinetics, mechanism and stability of tacrolimus in aqueous CD solutions, with the ultimate goal of developing an aqueous vehicle for ophthalmic delivery. For this, phase-solubility and kinetic studies in aqueous solutions containing different CDs at different pH values were performed. Mass spectrometry studies were also performed to elucidate the degradation mechanism of the drug in aqueous CD solution. The study showed that the drug has maximum stability between pH 4 and 6 and hydrolysis was the main cause of tacrolimus degradation in aqueous 2-hydroxypropyl-βCD (HPβCD) solutions. βCD and its derivatives were the better CD solubilizers for tacrolimus. The solubility and stability studies were further conducted with CD and surfactants, which is tyloxapol, tween 80 and poloxamer 407, where the combination provided better results compared to individual components.

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“…Third, the aqueous solution containing Tween-20 was used as the in vitro release medium. Sirolimus is very unstable in various aqueous solutions and has poor water solubility [ 58 , 59 , 60 , 61 ]. According to our previous work, the aqueous solution was supplemented by Tween-20 (4 g/L) to increase the stability and solubility of sirolimus, thereby attaining a favorable sink condition for the sirolimus release experiments [ 62 ].…”

Section: Resultsmentioning

confidence: 99%

The Effect of Fluid Shear Stress on the In Vitro Release Kinetics of Sirolimus from PLGA Films

Zheng

Chu

et al. 2017

Polymers

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Drug-carrying coatings of stents implanted in blood vessels are exposed to various blood flows. This study investigated the effect of fluid shear stress on the in vitro release kinetics of sirolimus from poly(lactic-co-glycolic acid) (PLGA) films. The homemade parallel plate flow chamber was used to exert quantitative shear stress on the sirolimus-carrying film. By adjusting the flow rate of the release media in the chamber, three levels of shear stress (3.6, 12.0, and 36.0 dyn/cm 2 ) were respectively applied. For each level of shear stress employed, the release kinetics of sirolimus from the PLGA films exhibited a four-phase profile: an initial burst release phase (Phase I), a lag phase (Phase II), a second burst release phase (Phase III), and a terminal release phase (Phase IV). During Phases I and II, sirolimus was released slowly and in small amounts (<10%); however, during Phases III and IV, the drug release increased considerably. Comparisons of different shear stresses indicated that greater shear stress resulted in earlier and faster sirolimus release, with more cumulative drug release observed. PLGA film degradations (molecular weight reduction, mass loss, and surface topographical variations) were also investigated to better explain the observed drug release behavior. Consequently, fluid shear stress was found to significantly accelerate the release of sirolimus from the PLGA matrices. Therefore, this study could provide a practical method for evaluating the in vitro drug release from polymer matrices under uniform shear stress, and might help improve the design of biodegradable coatings on drug-eluting stents.

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Degradation of rapamycin and its ring-opened isomer: Role of base catalysis

Cited by 25 publications

References 22 publications

Discovery of RMC-5552, a Selective Bi-Steric Inhibitor of mTORC1, for the Treatment of mTORC1-Activated Tumors

Discovery of RMC-5552, a Selective Bi-Steric Inhibitor of mTORC1, for the Treatment of mTORC1-Activated Tumors

Stability characterization, kinetics and mechanism of tacrolimus degradation in cyclodextrin solutions

The Effect of Fluid Shear Stress on the In Vitro Release Kinetics of Sirolimus from PLGA Films

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