5HCY: Egfr Kinase Domain Mutant "tmlr" With 3-carboxamide Azaindole Compound 13

Inhibitors targeting the activating mutants of the epidermal growth factor receptor (EGFR) have found success in the treatment of EGFR mutant positive non-small-cell lung cancer. A secondary point mutation (T790M) in the inhibitor binding site has been linked to the acquired resistance against those first generation therapeutics. Herein, we describe the lead optimization of a series of reversible, pan-mutant (L858R, del746-750, T790M/L858R, and T790M/del746-750) EGFR inhibitors. By use of a noncovalent double mutant (T790M/L858R and T790M/del746-750) selective EGFR inhibitor (2) as a starting point, activities against the single mutants (L858R and del746-750) were introduced through a series of structure-guided modifications. The in vitro ADME-PK properties of the lead molecules were further optimized through a number of rational structural changes. The resulting inhibitor (21) exhibited excellent cellular activity against both the single and double mutants of EGFR, demonstrating target engagement in vivo and ADME-PK properties that are suitable for further evaluation. The reversible, noncovalent inhibitors described complement the covalent pan-mutant EGFR inhibitors that have shown encouraging results in recent clinical trials.
PDB ID: 5HCYDownload
MMDB ID: 142811
PDB Deposition Date: 2016/1/4
Updated in MMDB: 2016/10
Experimental Method:
x-ray diffraction
Resolution: 2.46  Å
Source Organism:
Similar Structures:
Biological Unit for 5HCY: monomeric; determined by author and by software (PISA)
Molecular Components in 5HCY
Label Count Molecule
Protein (1 molecule)
Epidermal Growth Factor Receptor(Gene symbol: EGFR)
Molecule annotation
Chemicals (2 molecules)
* Click molecule labels to explore molecular sequence information.

Citing MMDB