Hypoxia-inducible factor 1.alpha. hif-1.alpha. variants and...

C - Chemistry – Metallurgy – 07 – K

Patent

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Details

C07K 14/47 (2006.01) C12N 5/10 (2006.01) C12N 15/12 (2006.01) A61K 38/00 (2006.01)

Patent

CA 2350830

The present invention relates to a method for identifying compounds capable of modulating the function of a functional domain of human HIF-1.alpha., said method comprising (i) contacting a candidate compound with a variant of human HIF-1.alpha., said variant essentially lacking at least one functional domain of human HIF-1.alpha., or having a mutation making at least one functional domain of human HIF-1.alpha. essentially inactive, said functional domain or domains being selected from the group consisting of (a) the PAS-B domain located in human HIF-1.alpha. between amino acids 178 and 390, (b) the C- terminal nuclear localization sequence (NLS) located in human HIF-1.alpha. essentially at amino acids 718 to 721, and (c) the transactivator / coactivator domain (N-TAD) located in human HIF-1.alpha. essentially between amino acids 531 to 584, and (d) the transactivator / coactivator domain (C- TAD) located in human HIF-1.alpha. essentially between amino acids 813 and 826, and (ii) determining the effect of the candidate compound on the said variant.

L'invention porte sur un procédé d'identification de composés susceptibles de moduler la fonction d'un domaine fonctionnel du HIF-1.alpha. humain ledit procédé consistant (i) à mettre en contact un composé candidat avec un variant du HIF-1.alpha. humain, ledit variant manquant au moins d'un domaine fonctionnel du HIF-1.alpha. humain, ou présentant une mutation rendant quasiment inactif l'un au moins des domaines du HIF-1.alpha. humain, le ou lesdits domaines fonctionnels étant sélectionnés parmi: (a) le domaine PAS-B situé dans le HIF-1.alpha. humain entre les acides aminés 178 et 390, (b) la séquence C-terminale (NLS) de localisation du noyau situé dans le HIF-1.alpha. humain essentiellement au niveau des acides aminés 718 à 721, et (c) le domaine transactivateur / coactivateur (N-TAD) situé dans le HIF-1.alpha. humain essentiellement entre les acides aminés 531 à 584, et (d) le domaine transactivateur / coactivateur (C-TAD) situé dans le HIF-1.alpha. humain essentiellement entre les acides aminés 813 et 826, puis (ii) à déterminer l'effet dudit composé candidat sur ledit variant.

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