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Discovery of Selective, Covalent FGFR4 Inhibitors with Antitumor Activity in Models of Hepatocellular Carcinoma
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2020-03-06 , DOI: 10.1021/acsmedchemlett.9b00601 Haibo Liu 1 , Deqiang Niu 1 , Robert Tjin Tham Sjin 1 , Alex Dubrovskiy 1 , Zhendong Zhu 1 , Joseph J McDonald 1 , Kelly Fahnoe 1 , Zhigang Wang 1 , Mark Munson 2 , Andrew Scholte 2 , Matthieu Barrague 2 , Maria Fitzgerald 2 , Jinyu Liu 2 , Michael Kothe 2 , Fangxian Sun 2 , Joshua Murtie 2 , Jie Ge 2 , Jennifer Rocnik 2 , Darren Harvey 2 , Beatriz Ospina 2 , Keli Perron 2 , Gang Zheng 2 , Elvis Shehu 2 , Laura Akullian D'Agostino 1
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2020-03-06 , DOI: 10.1021/acsmedchemlett.9b00601 Haibo Liu 1 , Deqiang Niu 1 , Robert Tjin Tham Sjin 1 , Alex Dubrovskiy 1 , Zhendong Zhu 1 , Joseph J McDonald 1 , Kelly Fahnoe 1 , Zhigang Wang 1 , Mark Munson 2 , Andrew Scholte 2 , Matthieu Barrague 2 , Maria Fitzgerald 2 , Jinyu Liu 2 , Michael Kothe 2 , Fangxian Sun 2 , Joshua Murtie 2 , Jie Ge 2 , Jennifer Rocnik 2 , Darren Harvey 2 , Beatriz Ospina 2 , Keli Perron 2 , Gang Zheng 2 , Elvis Shehu 2 , Laura Akullian D'Agostino 1
Affiliation
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Hepatocellular carcinoma (HCC) accounts for a majority of primary liver cancer and is one of the most common forms of cancer worldwide. Aberrant signaling of the FGF19-FGFR4 pathway leads to HCC in mice and is hypothesized to be a driver in FGF19 amplified HCC in humans. Multiple small molecule inhibitors have been pursued as targeted therapies for HCC in recent years, including several selective FGFR4 inhibitors that are currently being evaluated in clinical trials. Herein, we report a novel series of highly selective, covalent 2-amino-6,8-dimethyl-pyrido[2,3-d]pyrimidin-7(8H)-ones that potently and selectively inhibit FGFR4 signaling through covalent modification of Cys552, which was confirmed by X-ray crystallography. Correlative target occupancy and pFGFR4 inhibition were observed in vivo, as well as tumor regression in preclinical models of orthotopic and sorafenib-resistant HCC.
中文翻译：
在肝细胞癌模型中发现具有抗肿瘤活性的选择性共价 FGFR4 抑制剂
肝细胞癌 (HCC) 占原发性肝癌的大部分，是全球最常见的癌症形式之一。FGF19-FGFR4 通路的异常信号导致小鼠 HCC，并假设是人类 FGF19 扩增 HCC 的驱动因素。近年来，多种小分子抑制剂被用作 HCC 的靶向治疗，包括目前正在临床试验中评估的几种选择性 FGFR4 抑制剂。在此，我们报告了一系列新型的高选择性共价 2-amino-6,8-二甲基吡啶并[2,3 - d ]pyrimidin-7(8 H)-通过 Cys552 的共价修饰有效和选择性地抑制 FGFR4 信号传导，这已通过 X 射线晶体学证实。在体内观察到相关的靶标占有率和 pFGFR4 抑制，以及原位和索拉非尼耐药 HCC 的临床前模型中的肿瘤消退。
更新日期：2020-03-06
中文翻译：
在肝细胞癌模型中发现具有抗肿瘤活性的选择性共价 FGFR4 抑制剂
肝细胞癌 (HCC) 占原发性肝癌的大部分，是全球最常见的癌症形式之一。FGF19-FGFR4 通路的异常信号导致小鼠 HCC，并假设是人类 FGF19 扩增 HCC 的驱动因素。近年来，多种小分子抑制剂被用作 HCC 的靶向治疗，包括目前正在临床试验中评估的几种选择性 FGFR4 抑制剂。在此，我们报告了一系列新型的高选择性共价 2-amino-6,8-二甲基吡啶并[2,3 - d ]pyrimidin-7(8 H)-通过 Cys552 的共价修饰有效和选择性地抑制 FGFR4 信号传导，这已通过 X 射线晶体学证实。在体内观察到相关的靶标占有率和 pFGFR4 抑制，以及原位和索拉非尼耐药 HCC 的临床前模型中的肿瘤消退。
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