7JY4

hALK in complex with ((1S,2S)-1-(2,4-difluorophenyl)-2-(2-(3-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenoxy)cyclopropyl)methanamine

Summary for 7JY4

• Entry DOI: 10.2210/pdb7jy4/pdb
• Descriptor: ALK tyrosine kinase receptor, 1-{(1S,2S)-1-(2,4-difluorophenyl)-2-[2-(3-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenoxy]cyclopropyl}methanamine (3 entities in total)
• Functional Keywords: alk tyrosine kinase receptor, inhibitor, complex, kinase, sbdd, transferase-inhibitor complex, transferase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 36892.13

Authors

McGrath, A.P.,Zou, H.,Lane, W.,Saikatendu, K. (deposition date: 2020-08-28, release date: 2021-01-20, Last modification date: 2023-10-18)

Primary citation

Fujimori, I.,Wakabayashi, T.,Murakami, M.,Okabe, A.,Ishii, T.,McGrath, A.,Zou, H.,Saikatendu, K.S.,Imoto, H.
Discovery of Novel and Highly Selective Cyclopropane ALK Inhibitors through a Fragment-Assisted, Structure-Based Drug Design.
Acs Omega, 5:31984-32001, 2020

PubMed Abstract: Fragment screening is frequently used for hit identification. However, there was no report starting from a small fragment for the development of an anaplastic lymphoma kinase (ALK) inhibitor, despite the number of ALK inhibitors reported. We began our research with the fragment hit and our subsequent linker design, and its docking analysis yielded novel -1,2,2-trisubstituted cyclopropane . The fragment information was integrated with a structure-based approach to improve upon the selectivity over tropomyosin receptor kinase A, leading to the potent and highly selective ALK inhibitor, 4-trifluoromethylphenoxy--1,2,2-trisubstituted cyclopropane . This work shows that fragments become a powerful tool for both lead generation and optimization, such as the improvement of selectivity, by combining them with a structure-based drug design approach, resulting in the fast and efficient development of a novel, potent, and highly selective compound.

PubMed: 33344853
DOI: 10.1021/acsomega.0c04900

Experimental method

X-RAY DIFFRACTION (2.42 Å)