The mammalian target of rapamycin (mTOR) is a kinase that regulates cell growth, translational control, angiogenesis and cell survival by integrating nutrient and hormonal signals. As part of the mTORC1 and mTORC2 complexes, mTOR kinase plays a key role in several pathways that are frequently dysregulated in human cancer.
The TORC1/2 complex is an important therapeutic target because:
- TORC1/2 is a key intracellular point of convergence for a number of cellular signaling pathways (e.g., up and down-stream of Akt)
- It appears to be a stable target that does not mutate.
- Inhibiting mTOR may inhibit abnormal cell proliferation, tumor angiogenesis and abnormal cellular metabolism.
- TORC1/2 inhibitors have the potential for single agent efficacy.
- The role of mTOR in the PTEN/PI3K/ TSC/Akt/mTORC1/2 pathway offers compelling opportunities for biomarker-guided drug development.
The experience of rapamycin and its analogs ("rapalogs") provides a strong mechanistic rationale and clinical proof of concept for the therapeutic value of inhibiting mTOR. It also provides insight into how Intellikine's mechanistically novel, ATP-competitive mTOR inhibitors might demonstrate superior efficacy relative to the rapalogs for certain indications.
mTOR exists in two complexes, TORC1 and TORC2. TORC1 is activated by growth factor stimulation via the canonical PI3K-AKT-mTOR pathway and is sensitive to rapamycin. TORC1 connects nutrient, stress and hormone signaling via TSC and AMPK signaling components. TORC2 is thought to modulate growth factor signaling by direct phosphorylation (activation) of Akt, functioning as "PDK2". Rapamycin analogs do not acutely inhibit mTORC2 in most cells. Hence, cancer cells treated with rapamycin analogs usually display only partial inhibition of mTOR “complex” signaling and eventually increased phosphorylation of AKT due to loss of the feedback inhibitory circuit mediated by S6K, which can lead to enhanced survival and chemo-resistance.
Achievement: Intellikine has synthesized a class of inhibitors that represent potent, selective and ATP-competitive inhibitors of mTOR. Unlike rapamycin, our compounds inhibit both mTORC1 and mTORC2 and unlike reference compounds (e.g., pan PI3K inhibitors, GDC-0941 and BEZ-235), they inhibit mTOR with a high degree of selectivity relative to PI3Ks and protein kinases.