6JZ0
Crystal structure of EGFR kinase domain in complex with compound 78
Summary for 6JZ0
| Entry DOI | 10.2210/pdb6jz0/pdb |
| Descriptor | Epidermal growth factor receptor, E-4-(dimethylamino)-N-[3-[4-[[(1S)-2-oxidanyl-1-phenyl-ethyl]amino]-6-phenyl-furo[2,3-d]pyrimidin-5-yl]phenyl]but-2-enamide (3 entities in total) |
| Functional Keywords | kinase, atp binding site, covalent bonding with ligand, transferase-inhibitor complex, transferase/inhibitor |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 1 |
| Total formula weight | 37780.70 |
| Authors | Peng, Y.H.,Wu, J.S.,Wu, S.Y. (deposition date: 2019-04-30, release date: 2019-12-04, Last modification date: 2023-11-22) |
| Primary citation | Lin, S.Y.,Chang Hsu, Y.,Peng, Y.H.,Ke, Y.Y.,Lin, W.H.,Sun, H.Y.,Shiao, H.Y.,Kuo, F.M.,Chen, P.Y.,Lien, T.W.,Chen, C.H.,Chu, C.Y.,Wang, S.Y.,Yeh, K.C.,Chen, C.P.,Hsu, T.A.,Wu, S.Y.,Yeh, T.K.,Chen, C.T.,Hsieh, H.P. Discovery of a Furanopyrimidine-Based Epidermal Growth Factor Receptor Inhibitor (DBPR112) as a Clinical Candidate for the Treatment of Non-Small Cell Lung Cancer. J.Med.Chem., 62:10108-10123, 2019 Cited by PubMed Abstract: Epidermal growth factor receptor (EGFR)-targeted therapy in non-small cell lung cancer represents a breakthrough in the field of precision medicine. Previously, we have identified a lead compound, furanopyrimidine , which contains a ()-2-phenylglycinol structure as a key fragment to inhibit EGFR. However, compound showed high clearance and poor oral bioavailability in its pharmacokinetics studies. In this work, we optimized compound by scaffold hopping and exploiting the potent inhibitory activity of various warhead groups to obtain a clinical candidate, (DBPR112), which not only displayed a potent inhibitory activity against EGFR double mutations but also exhibited tenfold potency better than the third-generation inhibitor, osimertinib, against EGFR and HER2 exon 20 insertion mutations. Overall, pharmacokinetic improvement through lead-to-candidate optimization yielded fourfold oral AUC better that afatinib along with = 41.5%, an encouraging safety profile, and significant antitumor efficacy in in vivo xenograft models. DBPR112 is currently undergoing phase 1 clinical trial in Taiwan. PubMed: 31560541DOI: 10.1021/acs.jmedchem.9b00722 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.86 Å) |
Structure validation
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