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The cytosolic Hsp90-selective inhibitor TAS-116 has an acceptable safety profile and promising antitumor activity in clinical trials. We examined the binding characteristics of TAS-116 and its analogs to determine the impact of the ligand binding mode on selectivity for cytosolic Hsp90. Analyses of the co-crystal structure of Hsp90 and inhibitor TAS-116 suggest that TAS-116 interacts with the ATP-binding pocket, the ATP lid region, and the hydrophobic pocket. A competitive isothermal titration calorimetry analysis confirmed that a small fragment of TAS-116 (THS-510) docks into the lid region and hydrophobic pockets without binding to the ATP-binding pocket. THS-510 exhibited enthalpy-driven binding to Hsp90α and selectively inhibited cytosolic Hsp90 activity. The heat capacity change of THS-510 binding was positive, likely due to the induced conformational rearrangement of Hsp90. Thus, we concluded that interactions with the hydrophobic pocket of Hsp90 determine potency and selectivity of TAS-116 and derivatives for the cytosolic Hsp90 isoform.

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)-1 H-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.

A method for the synthesis of octalactin B is established via a new and quite effective mixed-anhydride lactonization for the synthesis of an eight-membered ring moiety using 2-methyl-6-nitrobenzoic anhydride with DMAP. Both an optically active linear precursor of the lactone and a side chain of octalactins are prepared by the enantioselective aldol reaction of ketene silyl acetals with aldehydes.

[Structure: see text] The total synthesis of pseudo 2-epibotcinolide (1b) through several featured synthetic approaches has been attained. First, the chiral linear precursors of the nine-membered ring compound is stereoselectively constructed by the asymmetric aldol reaction for producing beta-hydroxy ester units. Second, the key cyclization reaction to form the nine-membered lactone moiety is efficiently achieved by the extremely facile and powerful mixed-anhydride method promoted by 2-methyl-6-nitrobenzoic anhydride (MNBA) with basic promoters.

Octalactin A, an antitumor agent containing an eight-membered lactone moiety, has been stereoselectively prepared by means of enantioselective aldol reactions of selected silyl enolates with achiral aldehydes, promoted by a chiral Sn(II) complex. The medium-sized lactone part was effectively constructed by way of a new and rapid mixed-anhydride lactonization using 2-methyl-6-nitrobenzoic anhydride (MNBA) with a catalytic amount of 4-(dimethylamino)pyridine (DMAP) or 4-(dimethylamino)pyridine 1-oxide (DMAPO). The use of only 5 mol % of DMAP or 2 mol % of DMAPO rapidly promoted formation of the medium-sized ring of the octalactin, demonstrating the remarkable efficiency of the new lactonization protocol.

Various carboxylic esters are obtained at room temperature in excellent yields with high chemoselectivities from nearly equimolar amounts of carboxylic acids and alcohols using 2-methyl-6-nitrobenzoic anhydride with triethylamine by the promotion of a basic catalyst such as 4-(dimethylamino)pyridine. A variety of lactones are also prepared in high yields at room temperature from the corresponding omega-hydroxycarboxylic acids with use of 2-methyl-6-nitrobenzoic anhydride in the presence of 4-(dimethylamino)pyridine. A similar reaction occurs with triethylamine when using a catalytic amount of 4-(dimethylamino)pyridine 1-oxide as an effective promoter for the intramolecular condensation reaction. These methods are successfully applied to the synthesis of erythro-aleuritic acid lactone and an eight-membered-ring lactone moiety of octalactins A and B. The efficiency of the cyclizations is compared to those of other reported lactonizations.

Background: The molecular chaperone HSP90 has long been considered a promising target for cancer therapy; however, several HSP90 inhibitors have demonstrated excessive adverse effects in clinical trials potentially involving off-target and/or HSP90-related toxicities. TAS-116 is a novel, potent and orally active HSP90α/β inhibitor discovered by chemical optimization of an initial hit compound having a 4-(1H-indol-1-yl)benzamide core structure. Here we describe the structure evolution and biological evaluation of TAS-116. Results: Hit to lead investigations of a 4-(1H-indol-1-yl)benzamide derivative were accomplished by introduction of an alkyl group at the 3-position, inserting one or two nitrogen atoms into the indole ring and ring expansion. As a consequence of chemical structure evolution, we identified novel 5, 6- and 6, 6-fused heteroaromatic rings, especially, the pyrazolopyridine system, which showed increased HSP90-binding affinity in vitro, and cell growth inhibition with HSP90 client degradation. Regarding the 4-position of pyrazolopyridine, substituted imidazoles showed the most favorable profile in vitro inhibitory activities. As for the SAR of the benzamide moiety at the 2- and 3-position, introduction of alkyl and aminoalkyl groups at the 2- or 3-position showed favorable properties, in particular for oral absorption in mice. The clinical candidate, TAS-116, which was identified as a result of these chemistry efforts, showed potent and selective HSP90α/β inhibitory activities in vitro as well as good oral bioavailability in mice, rats and dogs. With regard to potential drug-drug interactions, TAS-116 did not inhibit major cytochrome P450 enzymes in vitro at effective concentrations of TAS-116. TAS-116 demonstrated tumor shrinkage in a NCI-N87 (human gastric cancer) xenograft model without significant body weight loss by oral administration. Preparation of TAS-116 analogues was accomplished through coupling reactions with 4-substituted-pyrazolopyridines which were prepared over several steps and appropriate benzonitriles. Conclusion: A novel, potent and orally active HSP90α/β selective inhibitor, TAS-116, was discovered by rational design and synthesis from a 4-(1H-indol-1-yl)benzamide derivative. The oral clinical candidate, TAS-116, shows favorable drug-like properties and warrants clinical development. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C127. Citation Format: Takao Uno, Makoto Kitade, Satoshi Yamashita, Hiromi Oshiumi, Yuichi Kawai, Takashi Mizutani, Chihoko Yoshimura, Yasuo Kodama, Hiromi Muraoka, Kouichi Takahashi, Kazuhiko Yonekura, Shuichi Ohkubo, Teruhiro Utsugi. TAS-116, an orally available HSP90α/β selective inhibitor: Synthesis and biological evaluation. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C127.