Figure 1.
Chemical strucures of the thiadiazole compounds and NVP-AUY922.
The Kd values for binding to Hsp90 are indicated.
Table 1.
Crystallographic statistics.
Figure 2.
PyMOL diagram showing binding interactions with Hsp90.
(A) Interactions of ICPD 34 and (B) ICPD 47 with the N-terminal domain of human Hsp90α. Dotted blue lines represent hydrogen bonds and the amino-acid residues involved are in green; cyan-colored spheres represent water molecules and cyan residues are amino acids solely in van der Waals contact. The structures for ICPD 34, and ICPD 47 were obtained at 2.5, and 1.4 Å resolution, respectively. ICPD 26, which lacks a 3-methoxy group relative to ICPD 34, binds in essentially the same manor as ICPD 34 and ICPD 47. For atomic coordinates and structure factors, see PDB codes 2YI0 (ICPD 26), 2YI5 (ICPD 34), and 2YI7 (ICPD 47).
Figure 3.
PyMol cartoons of the structure of human Hsp90-drug complexes.
(A), PyMol cartoon showing ICPD 34 (cyan) and NVP-AUY922 (yellow and magenta) bound to the N-terminal domain of human Hsp90α. The magenta region of the NVP-AUY922-Hsp90α complex represents the unstructured region of the ICPD 34-Hsp90α complex. The mobile loop region interacting with NVP-AUY922 is shown in gold. Water molecules are shown as cyan colored spheres and hydrogen bonds as dotted blue lines. The 3-methoxy group of ICPD 34 causes the loop represented by Asn 105 to Ile 110 to adopt an alternative conformation, which moves from the gold to green conformation. (B), Two orthogonal views of the superimposition of ICPD 34 (Cyan) and NVP-AUY922 (yellow) showing that the compounds bind with overall similarity, except for the morpholino group of NVP-AUY922 and the dimethoxyphenyl group of ICPD 34. The structures for ICPD 34 and NVP-AUY922 were obtained at 2.5 and 2.0 Å resolution, respectively. For atomic coordinates and structure factors, see PDB codes 2YI5 and 2VCI, respectively.
Table 2.
Hsp90 binding and inhibitory activities.
Figure 4.
The biomarker signature of Hsp90 inhibition.
Western blot showing depletion of Hsp90 client proteins and induction of Hsp72, Hsp27 and cleaved PARP, upon treatment with 1×, 5× and 10× GI50 concentrations of compounds in HCT116 human colon cancer cells for 24 hr. 17-AAG was used as a positive control. Gapdh was used as loading control. Induction of cleaved PARP is also shown and is indicative of apoptosis.