![Figure 3. Identification of the small molecule inhibitor AZ-TAK1. (A) Docked pose of AZ-TAK1 in TAK1 crystal structure. Binding mode of AZ-TAK1 (1-(2-(3-ethyl-5-(5-fluoro-4-(imidazo[1,2-b]pyridazin-3-yl)pyrimidin-2-ylamino)phenoxy)ethyl)piperidin-4-ol) is consistent with in house cocrystal structures of close analogs of AZ-TAK1 (Proteros Biostructures GmbH, unpublished work, August 10, 2008). AZ-TAK1 adopts a U-shaped conformation in TAK1, with the imidazopyridazine heterocycle packing atop C148 and aminopyrimidine making 2 hydrogen bond interactions with the hinge (A81). The 3-ethyl moiety points toward the sugar pocket and the 4-hydroxypiperidine is out in the solvent channel. (B) The ability of AZ-TAK1 to inhibit TAK1 kinase activity was measured in vitro with the use of a complex of recombinant TAK1 and TAB1 and the substrate MKK6kd. Data shown are representative of 3 independent assays. (C) Selectivity of AZ-TAK1 against a panel of 30 kinases.](https://ash.silverchair-cdn.com/ash/content_public/journal/blood/120/2/10.1182_blood-2011-07-369397/4/zh89991293810003.jpeg?Expires=1735843559&Signature=xOeai9t3gOydfLAcrf8bRDSAeo8kdQzc2xwUXcNUUoxOmmV0M0ybW1MP4IRnyPXPhQMDJyhSfMC1YSDmNMW440znP2vKJKmPx7UE720YCI~9qS6Roat8~NX3sfLaTQD0s8~1TvEmWJ8qmvLAAwlkILZLdtjIVbD~hyRG6h~IiQOBrBT71vHjGKAXoiuBf~JjEqeEQgTsWEZZq~hGWIwfzwUMIh-mZZ0x5iniDbON7P2Por5p7wEcOpS7AIIhRtJu2LHauCfYO0XeKDfgZQjykcZSrkUHAE2R~pTNeSi9RQ9H~YzRalEYDyIp8tmAy6nkDNsZyd2ZNSeoSc5kK6oEjw__&Key-Pair-Id=APKAIE5G5CRDK6RD3PGA)
Identification of the small molecule inhibitor AZ-TAK1. (A) Docked pose of AZ-TAK1 in TAK1 crystal structure. Binding mode of AZ-TAK1 (1-(2-(3-ethyl-5-(5-fluoro-4-(imidazo[1,2-b]pyridazin-3-yl)pyrimidin-2-ylamino)phenoxy)ethyl)piperidin-4-ol) is consistent with in house cocrystal structures of close analogs of AZ-TAK1 (Proteros Biostructures GmbH, unpublished work, August 10, 2008). AZ-TAK1 adopts a U-shaped conformation in TAK1, with the imidazopyridazine heterocycle packing atop C148 and aminopyrimidine making 2 hydrogen bond interactions with the hinge (A81). The 3-ethyl moiety points toward the sugar pocket and the 4-hydroxypiperidine is out in the solvent channel. (B) The ability of AZ-TAK1 to inhibit TAK1 kinase activity was measured in vitro with the use of a complex of recombinant TAK1 and TAB1 and the substrate MKK6kd. Data shown are representative of 3 independent assays. (C) Selectivity of AZ-TAK1 against a panel of 30 kinases.
