Related Experiment Video

Updated: Nov 2, 2025

Testing Targeted Therapies in Cancer using Structural DNA Alteration Analysis and Patient-Derived Xenografts
10:27

Testing Targeted Therapies in Cancer using Structural DNA Alteration Analysis and Patient-Derived Xenografts

Published on: July 25, 2020

7.5K

Chemical and Structural Strategies to Selectively Target mTOR Kinase

Chiara Borsari1, Martina De Pascale1, Matthias P Wymann1

  • 1Department of Biomedicine, University of Basel, Mattenstrasse 28, 4058, Basel, Switzerland.

Chemmedchem
|June 11, 2021
PubMed

Insights

Dysregulation of the mechanistic target of rapamycin (mTOR) pathway is linked to cancer and neurological disorders. This review explores ATP-competitive mTOR kinase inhibitors (TORKi) for potential therapeutic applications.

Area of Science:

  • Biochemistry
  • Medicinal Chemistry
  • Pharmacology

Background:

  • The mechanistic target of rapamycin (mTOR) pathway is crucial in cellular processes and its dysregulation is linked to cancer and neurological disorders.
  • Current treatments often involve first-generation mTOR inhibitors (rapalogs) that allosterically inhibit TORC1.
  • ATP-competitive inhibitors offer an alternative by directly targeting the mTOR catalytic site, inhibiting both TORC1 and TORC2.

Purpose of the Study:

  • To review chemical scaffolds investigated for developing selective ATP-competitive mTOR kinase inhibitors (TORKi).
  • To highlight medicinal chemistry efforts in overcoming challenges in designing TORKi, particularly the structural similarity to phosphoinositide 3-kinase (PI3K).
  • To discuss insights gained regarding chemical substitutions and physicochemical properties influencing blood-brain barrier (BBB) penetration.

Main Methods:

  • Review of published research on ATP-competitive mTOR kinase inhibitors (TORKi).
  • Analysis of medicinal chemistry strategies employed to achieve selectivity and target specific properties.
  • Examination of structure-activity relationships and physicochemical property investigations.

Main Results:

  • A broad chemical space has been explored for TORKi development.
  • Medicinal chemistry has successfully addressed challenges related to mTOR and PI3K structural homology.
  • Investigations have provided insights into optimizing TORKi for blood-brain barrier (BBB) penetration.

Conclusions:

  • ATP-competitive mTOR kinase inhibitors (TORKi) represent a promising therapeutic strategy for various human disorders.
  • Optimized TORKi could be developed for treating cancer and central nervous system disorders.
  • Further research into chemical scaffolds and properties is essential for advancing TORKi-based therapies.
Keywords:
BBB permeabilitybinding modeschemical scaffoldsmTOR inhibitorsphysicochemical properties

More Related Videos

A Semi-Quantitative Drug Affinity Responsive Target Stability DARTS assay for studying Rapamycin/mTOR interaction05:28

A Semi-Quantitative Drug Affinity Responsive Target Stability DARTS assay for studying Rapamycin/mTOR interaction

Published on: August 27, 2019

16.9K
Isolation of Primary Mouse Hepatocytes for Nascent Protein Synthesis Analysis by Non-radioactive L-azidohomoalanine Labeling Method08:04

Isolation of Primary Mouse Hepatocytes for Nascent Protein Synthesis Analysis by Non-radioactive L-azidohomoalanine Labeling Method

Published on: October 23, 2018

19.3K

Related Concept Videos

PI3K/mTOR/AKT Signaling Pathway01:22

PI3K/mTOR/AKT Signaling Pathway

The mammalian target of rapamycin  (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1  (mTORC1) and mTOR complex 2  (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast,  mTORC2 consists of a...
4.3K
mTOR Signaling and Cancer Progression03:03

mTOR Signaling and Cancer Progression

The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
4.0K
Targeted Cancer Therapies02:57

Targeted Cancer Therapies

The targeted cancer therapies, also known as “molecular targeted therapies,” take advantage of the molecular and genetic differences between the cancer cells and the normal cells. It needs a thorough understanding of the cancer cells to develop drugs that can target specific molecular aspects that drive the growth, progression, and spread of cancer cells without affecting the growth and survival of other normal cells in the body.
There are several types of targeted therapies against...
8.0K
MAPK Signaling Cascades01:07

MAPK Signaling Cascades

Mitogen-activated protein kinase, or MAPK pathway, activates three sequential kinases to regulate cellular responses such as proliferation, differentiation, survival, and apoptosis. The canonical MAPK pathway starts with a mitogen or growth factor binding to an RTK. The activated RTKs stimulate Ras, which recruits Raf or MAP3 Kinase (MAPKKK), the first kinase of the MAPK signaling cascade. Raf further phosphorylates and activates MEK or MAP2 Kinases (MAPKK), which in turn phosphorylates MAP...
6.8K
M-Cdk Drives Transition Into Mitosis02:15

M-Cdk Drives Transition Into Mitosis

Checkpoints throughout the cell cycle serve as safeguards and gatekeepers, allowing the cell cycle to progress in favorable conditions and slow or halt it in problematic ones. This regulation is known as the cell cycle control system.
Cyclin-dependent kinases, or Cdks, work in concert with cyclins to control cell cycle transitions. M-Cdk, a complex of Cdk1 bound to M cyclin, is a well-known example of this coordinated control that drives the transition from the G2 to the M phase.
M cyclin...
5.8K
Protein Kinases and Phosphatases02:54

Protein Kinases and Phosphatases

Proteins undergo chemical modifications that trigger changes in the charge, structure, and conformation of the proteins. Phosphorylation, acetylation, glycosylation, nitrosylation, ubiquitination, lipidation, methylation, and proteolysis are various protein modifications that regulate protein activity. Such modifications are usually enzyme-driven.
Protein kinases
Many proteins in the cell are regulated by phosphorylation, the addition of a phosphate group. A family of enzymes called kinases...
14.0K