Discovery of Novel 2-Aminobenzamide Inhibitors of Heat Shock Protein 90 as Potent, Selective and Orally Active Antitumor Agents

Abstract

A novel class of heat shock protein 90 (Hsp90) inhibitors was developed from an unbiased screen to identify protein targets for a diverse compound library. These indol-4-one and indazol-4-one derived 2-aminobenzamides showed strong binding affinity to Hsp90, and optimized analogues exhibited nanomolar antiproliferative activity across multiple cancer cell lines. Heat shock protein 70 (Hsp70) induction and specific client protein degradation in cells on treatment with the inhibitors supported Hsp90 inhibition as the mechanism of action. Computational chemistry and X-ray crystallographic analysis of selected member compounds clearly defined the protein-inhibitor interaction and assisted the design of analogues. 4-[6,6-Dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]-2-[(trans-4-hydroxycyclohexyl)amino]benzamide (SNX-2112, 9) was identified as highly selective and potent (IC(50) Her2 = 11 nM, HT-29 = 3 nM); its prodrug amino-acetic acid 4-[2-carbamoyl-5-(6,6-dimethyl-4-oxo-3-trifluoromethyl-4,5,6,7-tetrahydro-indazol-1-yl)-phenylamino]-cyclohexyl ester methanesulfonate (SNX-5422, 10) was orally bioavailable and efficacious in a broad range of xenograft tumor models (e.g. 67% growth delay in a HT-29 model) and is now in multiple phase I clinical trials.

Hsp90 Inhibitors as New Leads To Target Parasitic Diarrheal Diseases

“…A novel class of Hsp90 inhibitors, indol-4-one and indazol-4-one-derived 2-aminobenzamides, was synthesized following the methods described by Huang et al (37). The benzonitrile intermediates involved in the synthesis of the benzamides were also evaluated for activity.…”

“…1), the prodrug of SNX-2112, in mouse models of amebiasis and giardiasis. As the crystalline form of SNX-2112 was not orally bioavailable, we improved the kinetic solubility and bioavailability for oral dosing by using a glycine ester prodrug, SNX-5422, for animal studies (37,48). The advantage of using SNX-5422 in the mouse models is that full toxicological and pharmacokinetic profiles are available for this compound.…”

“…The advantage of using SNX-5422 in the mouse models is that full toxicological and pharmacokinetic profiles are available for this compound. The parameters calculated for a single 50 mg/kg dose in female mice were as follows: half-life (t 1/2 ) ϭ 3.3 h, maximum concentration of drug in serum (C max ) ϭ 4,015 ng/ml, time to C max (T max ) ϭ 2 h, and area under the concentration-time curve to infinity (AUC ϱ ) ϭ 25,153 h · ng/ml (37). No adverse effects related to SNX-5422 were observed for the mice dosed at 50 mg/kg 3 times a week for 3 weeks (37).…”

“…The parameters calculated for a single 50 mg/kg dose in female mice were as follows: half-life (t 1/2 ) ϭ 3.3 h, maximum concentration of drug in serum (C max ) ϭ 4,015 ng/ml, time to C max (T max ) ϭ 2 h, and area under the concentration-time curve to infinity (AUC ϱ ) ϭ 25,153 h · ng/ml (37). No adverse effects related to SNX-5422 were observed for the mice dosed at 50 mg/kg 3 times a week for 3 weeks (37). A single oral dose of 5 mg/kg/day of SNX-5422 for 7 days significantly decreased the burden of E. histolytica compared to the burden in control mice (P ϭ 0.0058) (Fig.…”

Efficient MW-Assisted Synthesis, Spectroscopic Characterization, X-ray and Antioxidant Properties of Indazole Derivatives

“…Tetrahydroindazole are potent medicinal scaffolds and exhibt a full spectrum of biological activities [13][14][15][16][17]. Due to their attractive pharmacological properties tetrahydroindazole derivatives have attracted the attention of chemists who have researched ways to obtain the desired properties through different synthetic strategies [18].…”