7ER2

Crystal structure of EGFR 696-1022 T790M/C797S in complex with LS_2_40

Summary for 7ER2

• Entry DOI: 10.2210/pdb7er2/pdb
• Descriptor: Epidermal growth factor receptor, 5-chloranyl-N2-[3-chloranyl-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl]-N4-(2-dimethylphosphorylphenyl)pyrimidine-2,4-diamine (3 entities in total)
• Functional Keywords: egfr, t790m/c797s, inhibitor, transferase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 38048.88

Authors

Zhu, S.J.,Yun, C.H. (deposition date: 2021-05-05, release date: 2022-04-20, Last modification date: 2023-11-29)

Primary citation

Li, S.,Zhang, T.,Zhu, S.J.,Lei, C.,Lai, M.,Peng, L.,Tong, L.,Pang, Z.,Lu, X.,Ding, J.,Ren, X.,Yun, C.H.,Xie, H.,Ding, K.
Optimization of Brigatinib as New Wild-Type Sparing Inhibitors of EGFR T790M/C797S Mutants.
Acs Med.Chem.Lett., 13:196-202, 2022

PubMed Abstract: A series of brigatinib derivatives were designed and synthesized as new potent and selective EGFR inhibitors. One of the most potent and selective compounds strongly suppressed the EGFR and EGFR kinases with IC values of 0.7 and 3.6 nM, respectively, which were over 54-fold more potent than the lead compound. also demonstrated promising EGFR mutant selectivity, and was 94-fold less potent against the wild type EGFR. A cocrystal structure of EGFR with a close derivative was solved to provide insight on the inhibitor's binding mode. Moreover, compound was orally bioavailable and demonstrated highly desirable PK properties, making it a promising lead compound for further structural optimization.

PubMed: 35178175
DOI: 10.1021/acsmedchemlett.1c00555

Experimental method

X-RAY DIFFRACTION (2.662 Å)