3R4P

Optimization of potent, selective, and orally bioavailable pyrrolodinopyrimidine-containing inhibitors of heat shock protein 90. identification of development candidate 2-amino-4-{4-chloro-2-[2-(4-fluoro-1H-pyrazol-1-yl)ethoxy]-6-methylphenyl}-N-(2,2-difluoropropyl)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxamide

Summary for 3R4P

• Entry DOI: 10.2210/pdb3r4p/pdb
• Related: 3R4M 3R4N 3R4O
• Descriptor: Heat shock protein HSP 90-alpha, 2-amino-4-{2,4-dichloro-6-[2-(1H-pyrazol-1-yl)ethoxy]phenyl}-N-(2,2-difluoropropyl)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxamide, PHOSPHATE ION, ... (4 entities in total)
• Functional Keywords: chaperone, atp binding, chaperone-chaperone inhibitor complex, chaperone/chaperone inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: P07900
• Total number of polymer chains: 2
• Total formula weight: 52475.29

Authors

Gajiwala, K.S. (deposition date: 2011-03-17, release date: 2011-04-27, Last modification date: 2024-02-21)

Primary citation

Zehnder, L.,Bennett, M.,Meng, J.,Huang, B.,Ninkovic, S.,Wang, F.,Braganza, J.,Tatlock, J.,Jewell, T.,Zhou, J.Z.,Burke, B.,Wang, J.,Maegley, K.,Mehta, P.P.,Yin, M.J.,Gajiwala, K.S.,Hickey, M.J.,Yamazaki, S.,Smith, E.,Kang, P.,Sistla, A.,Dovalsantos, E.,Gehring, M.R.,Kania, R.,Wythes, M.,Kung, P.P.
Optimization of potent, selective, and orally bioavailable pyrrolodinopyrimidine-containing inhibitors of heat shock protein 90. Identification of development candidate 2-amino-4-{4-chloro-2-[2-(4-fluoro-1H-pyrazol-1-yl)ethoxy]-6-methylphenyl}-N-(2,2-difluoropropyl)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxamide.
J.Med.Chem., 54:3368-3385, 2011

PubMed Abstract: A novel class of heat shock protein 90 (Hsp90) inhibitors was discovered by high-throughput screening and was subsequently optimized using a combination of structure-based design, parallel synthesis, and the application of medicinal chemistry principles. Through this process, the biochemical and cell-based potency of the original HTS lead were substantially improved along with the corresponding metabolic stability properties. These efforts culminated with the identification of a development candidate (compound 42) which displayed desired PK/PD relationships, significant efficacy in a melanoma A2058 xenograft tumor model, and attractive DMPK profiles.

PubMed: 21438541
DOI: 10.1021/jm200128m

Experimental method

X-RAY DIFFRACTION (1.7 Å)