5HCY

EGFR kinase domain mutant "TMLR" with 3-carboxamide azaindole compound 13

Summary for 5HCY

• Entry DOI: 10.2210/pdb5hcy/pdb
• Related: 5HCX 5HCZ
• Descriptor: Epidermal growth factor receptor, SULFATE ION, 6-[[2-(1-cyclopropylsulfonylpyrazol-4-yl)pyrimidin-4-yl]amino]-~{N}-(oxan-4-yl)-1-propan-2-yl-pyrrolo[3,2-c]pyridine-3-carboxamide, ... (4 entities in total)
• Functional Keywords: protein kinase, inhibitor, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Cell membrane; Single-pass type I membrane protein. Isoform 2: Secreted: P00533
• Total number of polymer chains: 1
• Total formula weight: 38196.09

Authors

Eigenbrot, C.,Yu, C. (deposition date: 2016-01-04, release date: 2016-09-07, Last modification date: 2024-03-06)

Primary citation

Chan, B.K.,Hanan, E.J.,Bowman, K.K.,Bryan, M.C.,Burdick, D.,Chan, E.,Chen, Y.,Clausen, S.,Dela Vega, T.,Dotson, J.,Eigenbrot, C.,Elliott, R.L.,Heald, R.A.,Jackson, P.S.,Knight, J.D.,La, H.,Lainchbury, M.D.,Malek, S.,Purkey, H.E.,Schaefer, G.,Schmidt, S.,Seward, E.M.,Sideris, S.,Shao, L.,Wang, S.,Yeap, S.K.,Yen, I.,Yu, C.,Heffron, T.P.
Discovery of a Noncovalent, Mutant-Selective Epidermal Growth Factor Receptor Inhibitor.
J.Med.Chem., 59:9080-9093, 2016

PubMed Abstract: 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, del T790M/L858R, and T790M/del) EGFR inhibitors. By use of a noncovalent double mutant (T790M/L858R and T790M/del) selective EGFR inhibitor (2) as a starting point, activities against the single mutants (L858R and del) 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.

PubMed: 27564586
DOI: 10.1021/acs.jmedchem.6b00995

Experimental method

X-RAY DIFFRACTION (2.46 Å)