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

Abstract

The molecular chaperone heat shock protein 90 (HSP90) is a promising target for cancer therapy, as it assists in the stabilization of cancer-related proteins, promoting cancer cell growth, and survival. A novel series of HSP90 inhibitors were discovered by structure–activity relationship (SAR)-based optimization of an initial hit compound 11a having a 4-(4-(quinolin-3-yl)-1H-indol-1-yl)­benzamide structure. The pyrazolo­[3,4-b]­pyridine derivative, 16e (TAS-116), is a selective inhibitor of HSP90α and HSP90β among the HSP90 family proteins and exhibits oral availability in mice. The X-ray cocrystal structure of the 16e analogue 16d demonstrated a unique binding mode at the N-terminal ATP binding site. Oral administration of 16e demonstrated potent antitumor effects in an NCI-H1975 xenograft mouse model without significant body weight loss.

Recent Progress Concerning the N-Arylation of Indoles

“…Another set of indole derivatives with a similar substitution at position 1 of the indole skeleton was reported by Tamoo [ 181 ] and Uno ( Figure 9 ) [ 182 ]. On the basis of extensive SAR studies, it was found that F9-1 is an inhibitor of cPLA 2α (with an IC 50 value of 0.075 μM) [ 181 ], and indole F9-2 is a selective inhibitor of both HSP90 (IC 50 = 0.069 μM) and SK-Br-3 (IC 50 = 0.33 μM) [ 182 ]. The introduction of the aryl substituents was accomplished via copper-catalyzed Ullman condensation at reaction temperatures above 100 °C.…”

HSP90 inhibitors reduce cholesterol storage in Niemann-Pick type C1 mutant fibroblasts

“…This may be due to the pleiotropic effects of HSP90 inhibition. The effective concentrations of the HSP90 inhibitors in this assay were generally comparable to values for blocking the growth of cancer cells in culture ( 49 , 50 , 52 , 53 , 54 ), although there was variability of the potency of the compounds in blocking different tumor cells. Detailed statistical analysis was performed using GraphPad Prism software, and the P values calculated using the ANOVA Kruskal-Wallis multiple comparison test are shown in supplemental Fig.…”

“…For instance, the reported IC 50 for ganetespib is 5 nM ( 59 ), and we see the half maximal effect at 5 nM. For TAS-116, the reported value is 69 nM ( 53 ), and we see the half maximal effect near that dose.

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“…We tested the effects of six HSP90 inhibitors on lysosomal cholesterol accumulation in NPC1 I1061T mutant human fibroblasts. Cells plated in 384-well plates were treated with 17-AAG ( 47 ), AUY922 ( 47 ), ganetespib ( 48 ), AT13387 ( 49 , 50 , 51 ), SNX2112 ( 52 ), or TAS-116 ( 53 ) at concentrations ranging from 0.5 nM to 10 μM depending on the reported potency of the compounds. The fibroblasts were treated with inhibitors for 72 h followed by fixation, staining with filipin and Draq5, and fluorescence microscopy analysis.…”

Imidazoles as Potential Anticancer Agents: An Update on Recent Studies

“…While a number of HSP90 inhibitors are undergoing clinical trials, there are currently no approved anticancer drugs that act on this pathway, highlighting the need for further investigation of small molecules targeting HSPs (see References [ 172 , 173 ] for reviews focusing on the targeting of HSPs and HSP90, respectively). Uno et al reported a series of molecules based on preliminary hit 190 as potential HSP90 inhibitors [ 174 ]. Compound 190 was a hybrid compound designed from the X-ray crystal structures of two previous inhibitors of HSP90.…”