Abstract C127: TAS-116, an orally available HSP90α/β selective inhibitor: Synthesis and biological evaluation.
Authors: Uno Takao , Kitade Makoto , Yamashita Satoshi , Oshiumi Hiromi , Kawai Yuichi , Mizutani Takashi , Yoshimura Chihoko , Kodama Yasuo , Muraoka Hiromi , Takahashi Kouichi , Yonekura Kazuhiko , Ohkubo Shuichi , Utsugi Teruhiro 
Published: August 2014

Abstract
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.