5HCX

EGFR kinase domain mutant "TMLR" with azabenzimidazole compound 7

5HCX の概要

• エントリーDOI: 10.2210/pdb5hcx/pdb
• 関連するPDBエントリー: 5HCY 5HCZ
• 分子名称: Epidermal growth factor receptor, SULFATE ION, ~{N}-[2-(1-cyclopropylsulfonylpyrazol-4-yl)pyrimidin-4-yl]-2-methyl-1-propan-2-yl-imidazo[4,5-c]pyridin-6-amine, ... (4 entities in total)
• 機能のキーワード: protein kinase, inhibitor, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Cell membrane; Single-pass type I membrane protein. Isoform 2: Secreted: P00533
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 38083.97

構造登録者

Eigenbrot, C.,Yu, C. (登録日: 2016-01-04, 公開日: 2016-09-07, 最終更新日: 2023-09-27)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.6 Å)