7LTX
EGFR (T790M/V948R) in complex with quinazolinone allosteric inhibitor
Summary for 7LTX
| Entry DOI | 10.2210/pdb7ltx/pdb |
| Descriptor | Epidermal growth factor receptor, PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER, MAGNESIUM ION, ... (5 entities in total) |
| Functional Keywords | egfr, kinase, allosteric, inhibitor, quinazolinone, transferase, transferase-inhibitor complex, transferase/inhibitor |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 4 |
| Total formula weight | 155235.00 |
| Authors | Beyett, T.S.,Eck, M.J. (deposition date: 2021-02-20, release date: 2022-02-23, Last modification date: 2023-10-18) |
| Primary citation | Gero, T.W.,Heppner, D.E.,Beyett, T.S.,To, C.,Azevedo, S.C.,Jang, J.,Bunnell, T.,Feru, F.,Li, Z.,Shin, B.H.,Soroko, K.M.,Gokhale, P.C.,Gray, N.S.,Janne, P.A.,Eck, M.J.,Scott, D.A. Quinazolinones as allosteric fourth-generation EGFR inhibitors for the treatment of NSCLC. Bioorg.Med.Chem.Lett., 68:128718-128718, 2022 Cited by PubMed Abstract: The C797S mutation confers resistance to covalent EGFR inhibitors used in the treatment of lung tumors with the activating L858R mutation. Isoindolinones such as JBJ-4-125-02 bind in an allosteric pocket and are active against this mutation, with high selectivity over wild-type EGFR. The most potent examples we developed from that series have a potential chemical instability risk from the combination of the amide and phenol groups. We explored a scaffold hopping approach to identify new series of allosteric EGFR inhibitors that retained good potency in the absence of the phenol group. The 5-F quinazolinone 34 demonstrated tumor regression in an H1975 efficacy model upon once daily oral dosing at 25 mg/kg. PubMed: 35378251DOI: 10.1016/j.bmcl.2022.128718 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.3 Å) |
Structure validation
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