Design and synthesis of novel small-molecule inhibitors of the hypoxia inducible factor pathway.
Design and synthesis of novel small-molecule inhibitors of the hypoxia inducible factor pathway.
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DOI：
10.1021/jm201018g
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发表时间：
2011-12-22
影响因子：
7.3
通讯作者：
Wang, Binghe
中科院分区：
文献类型：
--
作者：
Mooring, Suazette Reid;Jin, Hui;Devi, Narra S.;Jabbar, Adnan A.;Kaluz, Stefan;Liu, Yuan;Van Meir, Erwin G.;Wang, Binghe
低氧，即氧分压的降低，是实体瘤的显著特征。缺氧驱动肿瘤的恶性进展和转移，并参与肿瘤对放疗和化疗的抵抗。低氧激活低氧诱导因子（HIF）家族的转录因子，其诱导调节适应性生物过程（如无氧代谢、细胞运动和血管生成）的靶基因。临床证据表明，HIF-1的表达与患者预后不良密切相关，并且HIF-1的活化有助于恶性行为和治疗抗性。因此，HIF-1已成为小分子抑制的重要治疗靶点。在此，我们描述了抑制HIF-1信号通路的小分子的设计和合成。这些化合物中的许多在纳摩尔范围内表现出抑制活性。单独的机制研究表明，这些抑制剂不改变HIF-1水平，但通过与p300和CBP相互作用干扰HIF-1α/HIF-1β/p300/CBP复合物的形成。
Hypoxia, a reduction in partial oxygen pressure, is a salient property of solid tumors. Hypoxia drives malignant progression and metastasis in tumors and participates in tumor resistance to radio- and chemotherapies. Hypoxia activates the hypoxia-inducible factor (HIF) family of transcription factors, which induce target genes that regulate adaptive biological processes such as anaerobic metabolism, cell motility and angiogenesis. Clinical evidence has demonstrated that expression of HIF-1 is strongly associated with poor patient prognosis and activation of HIF-1 contributes to malignant behavior and therapeutic resistance. Consequently, HIF-1 has become an important therapeutic target for inhibition by small molecules. Herein, we describe the design and synthesis of small molecules that inhibit the HIF-1 signaling pathway. Many of these compounds exhibit inhibitory activity in the nanomolar range. Separate mechanistic studies indicate that these inhibitors do not alter HIF-1 levels, but interfere with the HIF-1α/HIF-1β/p300/CBP complex formation by interacting with p300 and CBP.
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DOI：
10.1158/1078-0432.ccr-08-3180
发表时间：
2009-10-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Narita T;Yin S;Gelin CF;Moreno CS;Yepes M;Nicolaou KC;Van Meir EG
通讯作者：
Van Meir EG
影响因子：
15
作者：
Nicolaou, KC;Pfefferkorn, JA;Lillig, JE
通讯作者：
Lillig, JE
影响因子：
2.1
作者：
EVANS, JM;STEMP, G
通讯作者：
STEMP, G
影响因子：
56.9
作者：
Bruick, RK;McKnight, SL
通讯作者：
McKnight, SL
影响因子：
45.3
作者：
Koukourakis, MI;Bentzen, SM;Harris, AL
通讯作者：
Harris, AL