High Performance Liquid Chromatographic Isolation and Spectroscopic Characterization of Metabolites from the Bile of Rats Receiving Rapamycin (Sirolimus) Intravenously

Wang, C. P.; Lim, Heng‐Keang; Chan, Keith; Scatina, JoAnn; Sisenwine, Samuel F.

doi:10.1080/10826079708006326

Cited by 3 publications

(1 citation statement)

References 9 publications

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“…Other bi-steric compounds, such as 30 , were also susceptible to a similar ring-opening process to yield significant amounts of a seco-species after dosing to rats (data not shown). Comparable seco-species are a well-known degradant from rapamycin itself (where it is known as secorapamycin 34 ), which forms in vivo, , under enzymatic processes (CYP 3A4) , and under basic conditions. ,, 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 ).…”

Section: Resultsmentioning

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: Resultsmentioning

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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Identification of a new metabolite of macrolide immunosuppressant, like rapamycin and SDZ RAD, using high performance liquid chromatography and electrospray tandem mass spectrometry

Hallensleben

Raida²,

Habermehl

2000

J. Am. Soc. Mass Spectrom.

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Previously unknown metabolites from the two macrolide immunosuppressants rapamycin (sirolimus) and SDZ RAD [40-O-(2-hydroxyethyl)rapamycin] obtained after in vitro incubation with human liver microsomes have been purified. Structure elucidation was performed by nanoelectrospray ionization tandem mass spectrometry applying low energy collision activated dissociation. This ionization method is, as shown here, a powerful tool to determine metabolic pathways by analysis of even low abundance products. Product ion spectra of the isolated metabolites indicate a new kind of biotransformation reaction for rapamycin and SDZ RAD. The proposed metabolic pathway starts with an ester hydrolysis which leads to a ring-opened structure. A dehydration on C33-C34 and a supplementary hydrogenation at C33-C34 result in a structure similar to the ring-opened isomer with an single bond at C33-C34.

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Unleashing the Power of Semi-Synthesis: The Discovery of Torisel®

Skotnicki

Abou‐Gharbia

2014

Orphan Drugs and Rare Diseases

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Natural products offer unique and creative opportunities for drug discovery. With their complex architecture and multi-faceted functionality, these secondary metabolites often display exquisite pharmacological profiles and properties. Accordingly, natural products provide versatile and innovative starting points to apply the tenets of medicinal chemistry. Rapamycin (Rapamune®) is a potent, polyketide immunosuppressive agent, produced by Streptomyces hygroscopicus. Rapamycin forms a complex with FKBP and mTOR that elicits its unique mechanism of action, central in a number of biological processes. It is approved for the treatment of transplantation rejection. As part of a programme aimed at the identification of novel rapamycin analogues, we have explored systematic semi-synthetic point modifications to functional groups at essential regions of the molecule. The medicinal chemistry design rationale and strategy is highlighted, culminating in the discovery of CCI-779 (temsirolimus, Torisel®). Torisel® was approved (USA, May 2007) for the treatment of advanced renal cell carcinoma.

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High Performance Liquid Chromatographic Isolation and Spectroscopic Characterization of Metabolites from the Bile of Rats Receiving Rapamycin (Sirolimus) Intravenously

Cited by 3 publications

References 9 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

Identification of a new metabolite of macrolide immunosuppressant, like rapamycin and SDZ RAD, using high performance liquid chromatography and electrospray tandem mass spectrometry

Unleashing the Power of Semi-Synthesis: The Discovery of Torisel®

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