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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
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2018-12-07 00:00:00 , DOI: 10.1021/acs.jmedchem.8b01085 Takao Uno 1 , Yuichi Kawai 1 , Satoshi Yamashita 1 , Hiromi Oshiumi 2 , Chihoko Yoshimura 1 , Takashi Mizutani 1 , Tatsuya Suzuki 1 , Khoon Tee Chong 1 , Kazuhiko Shigeno 1 , Mitsuru Ohkubo 1 , Yasuo Kodama 1 , Hiromi Muraoka 1 , Kaoru Funabashi 1 , Koichi Takahashi 1 , Shuichi Ohkubo 1 , Makoto Kitade 3
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2018-12-07 00:00:00 , DOI: 10.1021/acs.jmedchem.8b01085 Takao Uno 1 , Yuichi Kawai 1 , Satoshi Yamashita 1 , Hiromi Oshiumi 2 , Chihoko Yoshimura 1 , Takashi Mizutani 1 , Tatsuya Suzuki 1 , Khoon Tee Chong 1 , Kazuhiko Shigeno 1 , Mitsuru Ohkubo 1 , Yasuo Kodama 1 , Hiromi Muraoka 1 , Kaoru Funabashi 1 , Koichi Takahashi 1 , Shuichi Ohkubo 1 , Makoto Kitade 3
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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.
中文翻译：
3-乙基-4-（3-异丙基-4-（4-（1-甲基-1 H-吡唑-4-基）-1 H-咪唑-1-基）-1 H-吡唑并[3， 4- b ]吡啶-1-基）苯甲酰胺（TAS-116）作为有效，选择性和口服的HSP90抑制剂
分子伴侣热休克蛋白90（HSP90）是癌症治疗的有希望的目标，因为它有助于稳定与癌症相关的蛋白质，促进癌细胞的生长和存活。通过基于结构-活性关系（SAR）的具有4-（4-（喹啉-3-基）-1 H-吲哚-1-基）苯甲酰胺的初始命中化合物11a优化，发现了一系列新的HSP90抑制剂结构体。吡唑并[3,4- b ]吡啶衍生物16e（TAS-116）是HSP90家族蛋白中HSP90α和HSP90β的选择性抑制剂，在小鼠中可口服。16e类似物16d的X射线共晶体结构在N-末端ATP结合位点显示出独特的结合模式。口服16e在NCI-H1975异种移植小鼠模型中显示出有效的抗肿瘤作用，而体重没有明显减轻。
更新日期：2018-12-07
中文翻译：
3-乙基-4-（3-异丙基-4-（4-（1-甲基-1 H-吡唑-4-基）-1 H-咪唑-1-基）-1 H-吡唑并[3， 4- b ]吡啶-1-基）苯甲酰胺（TAS-116）作为有效，选择性和口服的HSP90抑制剂
分子伴侣热休克蛋白90（HSP90）是癌症治疗的有希望的目标，因为它有助于稳定与癌症相关的蛋白质，促进癌细胞的生长和存活。通过基于结构-活性关系（SAR）的具有4-（4-（喹啉-3-基）-1 H-吲哚-1-基）苯甲酰胺的初始命中化合物11a优化，发现了一系列新的HSP90抑制剂结构体。吡唑并[3,4- b ]吡啶衍生物16e（TAS-116）是HSP90家族蛋白中HSP90α和HSP90β的选择性抑制剂，在小鼠中可口服。16e类似物16d的X射线共晶体结构在N-末端ATP结合位点显示出独特的结合模式。口服16e在NCI-H1975异种移植小鼠模型中显示出有效的抗肿瘤作用，而体重没有明显减轻。
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