Related Experiment Video

Updated: Jan 20, 2026

Identification of Mediators of T-cell Receptor Signaling via the Screening of Chemical Inhibitor Libraries
08:49

Identification of Mediators of T-cell Receptor Signaling via the Screening of Chemical Inhibitor Libraries

Published on: January 22, 2019

9.5K

A Conformational Restriction Strategy for the Identification of a Highly Selective Pyrimido-pyrrolo-oxazine mTOR

Chiara Borsari1, Denise Rageot1, Alix Dall'Asen2

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

Journal of Medicinal Chemistry
|August 30, 2019
PubMed

Insights

Researchers developed a novel chemical scaffold for highly selective mTOR inhibitors, offering a promising new avenue for cancer treatment. Compound 12b demonstrates significant mTOR selectivity and favorable pharmacokinetic properties.

Area of Science:

  • Oncology
  • Medicinal Chemistry
  • Pharmacology

Background:

  • The mechanistic target of rapamycin (mTOR) is crucial for cell growth and tumor development, making it a key target in cancer therapy.
  • ATP-competitive mTOR kinase inhibitors (TORKi) offer potential advantages over rapamycin derivatives for treating various cancers.

Purpose of the Study:

  • To explore novel chemical spaces for generating TORKi using a conformational restriction approach.
  • To identify potent and selective mTOR inhibitors for potential cancer treatment.

Main Methods:

  • Utilized a conformational restriction strategy to design and synthesize novel compounds.
  • Conducted structure-activity relationship (SAR) studies to optimize inhibitor properties.
  • Performed pharmacokinetic and CYP450 reactive phenotyping studies to assess drug metabolism and distribution.

Main Results:

  • Identified compound 12b with approximately 450-fold selectivity for mTOR over class I PI3K isoforms.
  • Compound 12b exhibited good oral bioavailability and limited brain penetration in rats.
  • Demonstrated high metabolic stability of 12b, indicated by CYP450 reactive phenotyping.

Conclusions:

  • The tricyclic pyrimido-pyrrolo-oxazine moiety represents a novel and effective scaffold for developing highly selective mTOR inhibitors.
  • Compound 12b shows promising characteristics for further development as a cancer therapeutic agent.

More Related Videos

A High Content Imaging Assay for Identification of Botulinum Neurotoxin Inhibitors14:10

A High Content Imaging Assay for Identification of Botulinum Neurotoxin Inhibitors

Published on: November 14, 2014

9.0K
High-throughput Identification of Gene Regulatory Sequences Using Next-generation Sequencing of Circular Chromosome Conformation Capture 4C-seq09:06

High-throughput Identification of Gene Regulatory Sequences Using Next-generation Sequencing of Circular Chromosome Conformation Capture 4C-seq

Published on: October 5, 2018

10.8K

Related Concept Videos

Identification of Mediators of T-cell Receptor Signaling via the Screening of Chemical Inhibitor Libraries08:49

Identification of Mediators of T-cell Receptor Signaling via the Screening of Chemical Inhibitor Libraries

This paper uses a flow-cytometry-based assay to screen libraries of chemical inhibitors for the identification of inhibitors and their targets that influence T-cell receptor signaling. The methods described here can also be expanded for high-throughput...
9.5K
A High Content Imaging Assay for Identification of Botulinum Neurotoxin Inhibitors14:10

A High Content Imaging Assay for Identification of Botulinum Neurotoxin Inhibitors

Botulinum neurotoxin is one of the most potent toxins among Category-A biothreat agents, yet a post-exposure therapeutic is not available. The high content imaging approach is a powerful methodology for identifying novel inhibitors as it enables multiparameter screening using biologically relevant motor neurons, the primary target of this...
9.0K
Conformity01:20

Conformity

Conformity is the change in a person’s behavior to go along with the group, even if that person does not agree with the group.
47.9K
High-throughput Identification of Gene Regulatory Sequences Using Next-generation Sequencing of Circular Chromosome Conformation Capture (4C-seq)09:06

High-throughput Identification of Gene Regulatory Sequences Using Next-generation Sequencing of Circular Chromosome Conformation Capture (4C-seq)

The identification of physical interactions between genes and regulatory elements is challenging but has been facilitated by chromosome conformation capture methods. This modification to the 4C-seq protocol mitigates PCR bias by minimizing over-amplification of PCR templates and maximizes the mappability of reads by incorporating an addition restriction enzyme digest...
10.8K
Identification of EGFR and RAS Inhibitors using Caenorhabditis elegans08:12

Identification of EGFR and RAS Inhibitors using Caenorhabditis elegans

The genetically tractable nematode Caenorhabditis elegans can be used as a simple and inexpensive model for drug discovery. Described here is a protocol to identify anticancer therapeutics that inhibit the downstream signaling of RAS and EGFR...
3.4K
Nucleocapsid Annealing-Mediated Electrophoresis (NAME) Assay Allows the Rapid Identification of HIV-1 Nucleocapsid Inhibitors08:33

Nucleocapsid Annealing-Mediated Electrophoresis (NAME) Assay Allows the Rapid Identification of HIV-1 Nucleocapsid Inhibitors

This protocol describes NAME, an assay that allows the rapid identification of molecules able to inhibit in vitro the chaperone activities of HIV-1 nucleocapsid...
9.3K