2YKJ

Tricyclic series of Hsp90 inhibitors

Summary for 2YKJ

• Entry DOI: 10.2210/pdb2ykj/pdb
• Related: 1BYQ 1OSF 1UY6 1UY7 1UY8 1UY9 1UYC 1UYD 1UYE 1UYF 1UYG 1UYH 1UYI 1UYK 1UYL 1YC1 1YC3 1YC4 1YER 1YES 1YET 2BSM 2BT0 2BUG 2BYH 2BYI 2BZ5 2C2L 2CCS 2CCT 2CCU 2CDD 2FWY 2FWZ 2JJC 2UWD 2VCI 2VCJ 2WI1 2WI2 2WI3 2WI4 2WI5 2WI6 2WI7 2XAB 2XDK 2XDL 2XDS 2XDU 2XDX 2XHR 2XHT 2XHX 2XJG 2XJJ 2XJX 2XK2 2YE2 2YE3 2YE4 2YE5 2YE6 2YE7 2YE8 2YE9 2YEA 2YEB 2YEC 2YED 2YEE 2YEF 2YEG 2YEH 2YEI 2YEJ 2YI0 2YI5 2YI6 2YI7 2YJX 2YK2 2YK9 2YKB 2YKC 2YKE 2YKI
• Descriptor: HEAT SHOCK PROTEIN HSP 90-ALPHA, 2-AMINO-N-[4-(3H-IMIDAZO[4,5-C]PYRIDIN-2-YL)--9H-FLUOREN-9-YL]-ISONICOTINAMIDE (3 entities in total)
• Functional Keywords: chaperone, inhibition
• Biological source: HOMO SAPIENS (HUMAN)
• Total number of polymer chains: 1
• Total formula weight: 23779.94

Authors

Dupuy, A.,Vallee, F. (deposition date: 2011-05-27, release date: 2011-10-19, Last modification date: 2024-05-08)

Primary citation

Vallee, F.,Carrez, C.,Pilorge, F.,Dupuy, A.,Parent, A.,Bertin, L.,Thompson, F.,Ferrari, P.,Fassy, F.,Lamberton, A.,Thomas, A.,Arrebola, R.,Guerif, S.,Rohaut, A.,Certal, V.,Ruxer, J.M.,Delorme, C.,Jouanen, A.,Dumas, J.,Grepin, C.,Combeau, C.,Goulaouic, H.,Dereu, N.,Mikol, V.,Mailliet, P.,Minoux, H.
Tricyclic Series of Heat Shock Protein 90 (Hsp90) Inhibitors Part I: Discovery of Tricyclic Imidazo[4,5-C]Pyridines as Potent Inhibitors of the Hsp90 Molecular Chaperone.
J.Med.Chem., 54:7206-7219, 2011

PubMed Abstract: A novel class of heat shock protein 90 (Hsp90) inhibitors was developed after a low throughput screen (LTS) of a focused library containing approximately 21K compounds selected by virtual screening. The initial [1-{3-H-imidazo[4-5-c]pyridin-2-yl}-3,4-dihydro-2H-pyrido[2,1-a]isoindole-6-one] (1) compound showed moderate activity (IC(50) = 7.6 μM on Hsp82, the yeast homologue of Hsp90). A high-resolution X-ray structure shows that compound 1 binds into an "induced" hydrophobic pocket, 10-15 Å away from the ATP/resorcinol binding site. Iterative cycles of structure-based drug design (SBDD) and chemical synthesis led to the design and preparation of analogues with improved affinity. These optimized molecules make productive interactions within the ATP binding site as reported by other Hsp90 inhibitors. This resulted in compound 8, which is a highly potent inhibitor in biochemical and cellular assays (K(d) = 0.35 nM on Hsp90; IC(50) = 30 nM on SKBr3 mammary carcinoma cells) and in an in vivo leukemia model.

PubMed: 21972823
DOI: 10.1021/JM200784M

Experimental method

X-RAY DIFFRACTION (1.46 Å)