Correction to 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

Discovery of 3-Ethyl-4-(3-isopropyl-4-(4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl)benzamide (TAS-116) as a Potent, Selective, and Orally Available HSP90 Inhibitor

“…On the basis of these results, the 16e (TAS-116) analogue 16d was considered to have a unique binding mode that has not been observed in the typical firstand second-generation HSP90 inhibitors. 30 The hydrogen bond with Tyr139 and water-mediated hydrogen bond network with Gln23 were observed in other HSP90 inhibitors by Valleé et al 40 On the basis of its promising HSP90 inhibitory activity and oral availability profile, the in vitro profile and PK properties of compound 16e were characterized. 41 Compound 16e selectively binds to HSP90α/β than to the highly homologous HSP90 family proteins GRP94 and TRAP1, as determined by the fluorescence polarization competitive binding assay with geldanamycin-fluorescein isothiocyanate.…”

Estimation of Protein–Ligand Unbinding Kinetics Using Non-Equilibrium Targeted Molecular Dynamics Simulations

“…In order to gain a systematic understanding of the impact of different molecular discriminants on binding kinetics, and thus help to establish a knowledge basis necessary for the rational design of compounds with desired kinetics, we performed a combined experimental and theoretical analysis on the dynamics of unbinding of two series of compounds with different chemical scaffolds (see Figure 1) bound to the ATPbinding N-terminal domain of the chaperone heat shock protein 90 (Hsp90, Figure 1C), 14−16 which is a well-known target for anticancer drugs. 14,17−19 On the basis of data shared within the Kinetics for Drug Discovery consortium (K4DD, www.k4dd.eu) 7,20,21 and pre-existing data sets, 19,22,23 we included a total of 26 compounds in the present analysis, which are listed in Table 1. Additionally, we determined by Xray crystallography the structures of one further protein−ligand complex (see Tables 1 and S2) and measured ligand binding kinetics and affinities of three further compounds via surface plasmon resonance (SPR).…”

“…Additionally, we determined by Xray crystallography the structures of one further protein−ligand complex (see Tables 1 and S2) and measured ligand binding kinetics and affinities of three further compounds via surface plasmon resonance (SPR). In detail, we investigated 14 compounds with a resorcinol backbone (compounds 1a−1n, see Figure 1; among them the Hsp90 inhibitor Ganetespib 24 1c), 11 compounds with N-heterocycle functionalities 19 (compounds 2a−2k), and the macrocyclic lactam Hsp90 inhibitor 17-DMAG, 18 17. Figure 1C displays an overview of the N-terminal domain of Hsp90 with bound compound 1f.…”

IFPTarget: A Customized Virtual Target Identification Method Based on Protein–Ligand Interaction Fingerprinting Analyses

“…The IFP model shown in Figure 1a was generated from the crystal structure of heat shock protein 90 (HSP90) complexed with a tricyclic inhibitor (PDB ID: 2YKC). 33 The interactions observed from this structure involve Tyr139 and Thr184 acting as hydrogen-bonding donors, Asn51 and Leu103 acting as hydrogen-bonding acceptors, face-to-face π−π stacking interactions from Phe138, edge-to-face π−π stacking interactions from Trp162, and hydrophobic interactions from Met98, Leu107, Phe138, Tyr139, and Trp162. Similarly, the IFP model (Figure 1b) generated from the crystal structure of leukotriene A4 hydrolase (LTA4H) with bound inhibitor RB3040 (PDB ID: 3B7R) 34 represents an interaction pattern involving Gly268, Gly269, Tyr383, and Arg563 acting as hydrogen-bonding donors, Glu271 and Tyr378 acting as hydrogen-bonding acceptors, positively charged interactions from Arg563 and Lys565, negatively charged interactions from Glu271 and Glu318, hydrophobic interactions from Val292 and His295, and metal-binding interactions from the catalytically important zinc ion.…”

“…Two examples of reference IFP models generated from the complex structures of (a) HSP90 with a tricyclic inhibitor (PDB ID: 2YKC) 33 and (b) LTA4H with RB3040 (PDB ID: 3B7R). 34 The two reference IFP models are shown in the box, representing interaction patterns involving eight types of important protein−ligand interactions, including D (hydrogen-bonding donor), A (hydrogenbonding acceptor), P (positively charged feature), N (negatively charged feature), F (face-to-face π−π stacking interaction), E (edge-toface π−π stacking interaction), H (hydrophobic interaction), and M (metal-binding interaction).…”