The mammalian target of rapamycin (mTOR) regulates cell growth and survival by integrating nutrient and hormonal signals. mTOR exists in two complexes, mTORC1 and mTORC2, which have distinct functions and are differentially sensitive to rapamycin. mTORC1 is sensitive to rapamycin and is activated by growth factors via the PI3K-Akt-mTOR pathway, while mTORC2 is resistant to rapamycin. mTORC2 is thought to phosphorylate Akt at S473, a key site for Akt activation. However, the role of mTORC2 in Akt phosphorylation remains controversial due to conflicting results from genetic and pharmacological studies. This study investigates the effects of two novel mTOR kinase domain inhibitors, TORKinibs (PP242 and PP30), on mTOR signaling. Unlike rapamycin, which inhibits mTORC1, TORKinibs inhibit both mTORC1 and mTORC2. The study shows that TORKinibs effectively inhibit Akt phosphorylation at S473 and T308, which are critical for Akt activation. PP242, in particular, inhibits cap-dependent translation more effectively than rapamycin, suggesting that it targets mTORC1 more efficiently. The findings indicate that mTORC1 has functions that are resistant to rapamycin but can be effectively inhibited by TORKinibs. The study also demonstrates that TORKinibs inhibit the proliferation of primary cells more completely than rapamycin. PP242 is a more effective inhibitor of mTORC1 than rapamycin and inhibits cap-dependent translation under conditions where rapamycin has no effect. These results suggest that TORKinibs are more effective than rapamycin in targeting mTOR and its role in cell growth and survival. The study highlights the importance of understanding the distinct functions of mTORC1 and mTORC2 and the potential of TORKinibs as a new class of mTOR inhibitors for studying mTOR's role in normal physiology and disease.The mammalian target of rapamycin (mTOR) regulates cell growth and survival by integrating nutrient and hormonal signals. mTOR exists in two complexes, mTORC1 and mTORC2, which have distinct functions and are differentially sensitive to rapamycin. mTORC1 is sensitive to rapamycin and is activated by growth factors via the PI3K-Akt-mTOR pathway, while mTORC2 is resistant to rapamycin. mTORC2 is thought to phosphorylate Akt at S473, a key site for Akt activation. However, the role of mTORC2 in Akt phosphorylation remains controversial due to conflicting results from genetic and pharmacological studies. This study investigates the effects of two novel mTOR kinase domain inhibitors, TORKinibs (PP242 and PP30), on mTOR signaling. Unlike rapamycin, which inhibits mTORC1, TORKinibs inhibit both mTORC1 and mTORC2. The study shows that TORKinibs effectively inhibit Akt phosphorylation at S473 and T308, which are critical for Akt activation. PP242, in particular, inhibits cap-dependent translation more effectively than rapamycin, suggesting that it targets mTORC1 more efficiently. The findings indicate that mTORC1 has functions that are resistant to rapamycin but can be effectively inhibited by TORKinibs. The study also demonstrates that TORKinibs inhibit the proliferation of primary cells more completely than rapamycin. PP242 is a more effective inhibitor of mTORC1 than rapamycin and inhibits cap-dependent translation under conditions where rapamycin has no effect. These results suggest that TORKinibs are more effective than rapamycin in targeting mTOR and its role in cell growth and survival. The study highlights the importance of understanding the distinct functions of mTORC1 and mTORC2 and the potential of TORKinibs as a new class of mTOR inhibitors for studying mTOR's role in normal physiology and disease.