Rapamycin analogs

Everolimus (40 Afinitor Novartis, 2009), a rapamycin analog, is the 42-0-(2-hydroxyethyl) derivative of sirolimus (34), and is marketed as an immunosuppressant by Novartis under the tradename Afinitor for use in advanced renal cell carcinoma.In March 2009, the FDA approved everolimus (40) for use against advanced renal cell carcinoma after failure of treatment with sunitinib or sorafenib. The drug works similarly to sirolimus as an inhibitor of mTOR (mammalian target of rapamycin), a serine-threonine kinase, downstream of the PI3K/AKT pathway. Everolimus (40) binds to an intracellular protein, EKBP-12, resulting in an inhibitory... 

Chen Y, BriU GM, Benz NJ, Leanna MR, Dhaon MK, Rasmussen M, Zhou CC, Bruzek JA, Bellettini JR. (2007) Normal phase and reverse phase HPLC-UV-MS analysis of process impurities for rapamycin analog... 

Bayle JH, Grimley JS, Stankunas K, Gestwicki JE, Wandless TJ, Crabtree GR. Rapamycin analogs with differential binding specificity permit orthogonal control of protein activity. Chem. Biol. 2006 13 99-107. 

CCI-779, a rapamycin analog and multifaceted inhibitor of signal transduction a phase I study. Proc. Am. Soc. Clin. Oncol. 19 726 (Abstr.)... 

Crabtree, Rapamycin analogs with differential binding specificity permit orthogonal control of protein activity,... 

The activation of both processes involves mammahan target of rapamycin-dependent (e.g., by rapamycin analog CCI-779) or -independent (e.g., by lithium and calpain inhibitors) pathways. Combination treatment of these processes provides additive protection against polyQ-mediated-related neurodegeneration (Sarkar et al., 2008). 

The second class of mTOR inhibitors is comprised of small molecules that directly interact at the ATP-binding site of mTOR. In contrast to rapamycin and its analogs, these compounds inhibit both functional complexes of mTOR, mTORCl and mTORC2. The dual inhibition of both complexes may have potential clinical benefits, as inhibition solely of mTORCl has been correlated with a negative feedback mechanism,120 and there is evidence that certain mTORCl functions are not fully inhibited by sirolimus.121 Relative to the rapalogs, the members of this second class of mTOR compounds are a newer entry to the field and have only recently begun clinical trials. 

Manipulation of the DEBS system has led to the most impressive demonstration of combinatorial biosynthesis to date. McDaniel and coworkers have utilized specific module-swapping strategies to access a variety of 6-deoxyerythronolide B analogs with modifications at each carbon of the macrolide backbone [26]. Modules 1-6 of DEBS were systematically replaced with individual rapamycin synthase components to alter oxidation state and methylation in the final polyketide product. The study produced 60 unique structures at yields ranging from 1 to 70% of that of 6-deoxyerythronolide B (Fig. 9.2-5). However, each new compound required independent synthase engineering, which made library construction quite tedious. 

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