The mammalian target of rapamycin (mTOR) regulates cell growth and survival by integrating nutrient and hormonal signals through two distinct complexes, mTORC1 and mTORC2. mTORC1 is sensitive to the selective inhibitor rapamycin and is activated by growth factor stimulation via the PI3K-Akt pathway, while mTORC2 is resistant to rapamycin. The study investigates two novel and specific mTOR kinase domain inhibitors, PP242 and PP30 (referred to as TORKinibs), which inhibit both mTORC1 and mTORC2. Unlike rapamycin, these inhibitors block the phosphorylation of Akt at S473 and prevent its full activation, and they inhibit proliferation of primary cells more effectively than rapamycin. Surprisingly, the enhanced activity of TORKinibs is not due to their inhibition of mTORC2, but rather to their more effective inhibition of mTORC1. PP242 specifically inhibits cap-dependent translation under conditions where rapamycin has no effect. These findings identify new functional features of mTORC1 that are resistant to rapamycin but effectively targeted by TORKinibs, providing new tools for studying mTOR and its role in normal physiology and human disease.The mammalian target of rapamycin (mTOR) regulates cell growth and survival by integrating nutrient and hormonal signals through two distinct complexes, mTORC1 and mTORC2. mTORC1 is sensitive to the selective inhibitor rapamycin and is activated by growth factor stimulation via the PI3K-Akt pathway, while mTORC2 is resistant to rapamycin. The study investigates two novel and specific mTOR kinase domain inhibitors, PP242 and PP30 (referred to as TORKinibs), which inhibit both mTORC1 and mTORC2. Unlike rapamycin, these inhibitors block the phosphorylation of Akt at S473 and prevent its full activation, and they inhibit proliferation of primary cells more effectively than rapamycin. Surprisingly, the enhanced activity of TORKinibs is not due to their inhibition of mTORC2, but rather to their more effective inhibition of mTORC1. PP242 specifically inhibits cap-dependent translation under conditions where rapamycin has no effect. These findings identify new functional features of mTORC1 that are resistant to rapamycin but effectively targeted by TORKinibs, providing new tools for studying mTOR and its role in normal physiology and human disease.