6JZ0

Crystal structure of EGFR kinase domain in complex with compound 78

6JZ0 の概要

• エントリーDOI: 10.2210/pdb6jz0/pdb
• 分子名称: 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)
• 機能のキーワード: kinase, atp binding site, covalent bonding with ligand, transferase-inhibitor complex, transferase/inhibitor
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 37780.70

構造登録者

Peng, Y.H.,Wu, J.S.,Wu, S.Y. (登録日: 2019-04-30, 公開日: 2019-12-04, 最終更新日: 2023-11-22)

主引用文献

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

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: 31560541
DOI: 10.1021/acs.jmedchem.9b00722

実験手法

X-RAY DIFFRACTION (2.86 Å)