41-Azido-41-de­oxy­rapamycin

The title compound, C51H78N4O12, is a derivative of rapamycin, a triene macrolide anti­biotic mol­ecule isolated from Streptomyces hygroscopicus. The macrocyclic ring structure has 15 chiral centres, with one of the substituent hy­droxy groups giving an intra­molecular hydrogen bond to a ketone O-atom acceptor. The mol­ecules also form inter­molecular hy­droxy–ketone O—H⋯O hydrogen-bonding associations, giving one-dimensional chains extending along (010). The crystal has 108 Å3 solvent-accessible voids

Uncoupling TORC2 from AGC kinases inhibits tumour growth

Cancer Research UK, the Francis Crick Institute and Barts Cancer Institute

Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR Cascade Inhibitors: How Mutations Can Result in Therapy Resistance and How to Overcome Resistance

The Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR cascades are often activated by genetic alterations in upstream signaling molecules such as receptor tyrosine kinases (RTK). Integral components of these pathways, Ras, B-Raf, PI3K, and PTEN are also activated/inactivated by mutations. These pathways have profound effects on proliferative, apoptotic and differentiation pathways. Dysregulation of these pathways can contribute to chemotherapeutic drug resistance, proliferation of cancer initiating cells (CICs) and premature aging. This review will evaluate more recently described potential uses of MEK, PI3K, Akt and mTOR inhibitors in the proliferation of malignant cells, suppression of CICs, cellular senescence and prevention of aging. Ras/Raf/MEK/ERK and Ras/PI3K/PTEN/Akt/mTOR pathways play key roles in the regulation of normal and malignant cell growth. Inhibitors targeting these pathways have many potential uses from suppression of cancer, proliferative diseases as well as aging