Chemical and Structural Strategies to Selectively Target mTOR Kinase

Abstract

Dysregulation of the mechanistic target of rapamycin (mTOR) pathway is implicated in cancer and neurological disorder, which identifies mTOR inhibition as promising strategy for the treatment of a variety of human disorders. First-generation mTOR inhibitors include rapamycin and its analogues (rapalogs) which act as allosteric inhibitors of TORC1. Structurally unrelated, ATP-competitive inhibitors that directly target the mTOR catalytic site inhibit both TORC1 and TORC2. Here, we review investigations of chemical scaffolds explored for the development of highly selective ATP-competitive mTOR kinase inhibitors (TORKi). Extensive medicinal chemistry campaigns allowed to overcome challenges related to structural similarity between mTOR and the phosphoinositide 3-kinase (PI3K) family. A broad region of chemical space is covered by TORKi. Here, the investigation of chemical substitutions and physicochemical properties has shed light on the compounds' ability to cross the blood brain barrier (BBB). This work provides insights supporting the optimization of TORKi for the treatment of cancer and central nervous system disorders.

ATM-SPARK: A GFP phase separation–based activity reporter of ATM

“…We next examined whether the observed effect of BGT226 is due to its inhibitory activity against ATM or mTOR/PI3K. We compared the effect of BGT226 with another PI3K/mTOR inhibitor VS-5584 that has similar or stronger effect in inhibiting PI3K and mTOR but no inhibition against ATM ( 37 ). We found that BGT226 but not VS-5584 sensitizes growth inhibition of cancer cells in response to NCS treatment (fig.…”

Computational Investigation of Isoxazole‐Based Molecules as Potential Drug‐Resistant Anti‐Tuberculosis H37Rv.

“…SuissADME platform [13] offers the synthetic accessibility coefficient of the proposed drug candidates. A compound is straightforward to synthesize if its coefficient is equal to 1 and very difficult to synthesize if this coefficient is equal to 10 [14] …”

“…A compound is straightforward to synthesize if its coefficient is equal to 1 and very difficult to synthesize if this coefficient is equal to 10. [14] Using Lipinski and Veber's rules, the similarity descriptors to the selected drugs were calculated with SwissADME.…”

The allosteric mechanism of mTOR activation can inform bitopic inhibitor optimization

“…mTOR drug discovery mTOR is a compelling drug target, with recent advances garnering increasing attention. 34,64,[83][84][85][86] Beyond fundamental therapeutic indices such as solubility, affinity, and broad kinase toxicity with off-target effects, ensuring high selectivity for mTORC1 over mTORC2 is critical. mTORC2 inhibition has been associated with compromised insulin sensitivity and glucose intolerance.…”