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Discovery of 1-(1H-Pyrazolo[4,3-c]pyridin-6-yl)urea Inhibitors of Extracellular Signal-Regulated Kinase (ERK) for the Treatment of Cancers
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2016-07-01 00:00:00 , DOI: 10.1021/acs.jmedchem.6b00708 Jongwon Lim 1 , Elizabeth H. Kelley 1 , Joey L. Methot 1 , Hua Zhou 1 , Alessia Petrocchi 1 , Hongmin Chen 1 , Susan E. Hill 1 , Marlene C. Hinton 1 , Alan Hruza 1 , Joon O. Jung 1 , John K. F. Maclean 1 , My Mansueto 1 , George N. Naumov 1 , Ulrike Philippar 1 , Shruti Raut 1 , Peter Spacciapoli 1 , Dongyu Sun 1 , Phieng Siliphaivanh 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2016-07-01 00:00:00 , DOI: 10.1021/acs.jmedchem.6b00708 Jongwon Lim 1 , Elizabeth H. Kelley 1 , Joey L. Methot 1 , Hua Zhou 1 , Alessia Petrocchi 1 , Hongmin Chen 1 , Susan E. Hill 1 , Marlene C. Hinton 1 , Alan Hruza 1 , Joon O. Jung 1 , John K. F. Maclean 1 , My Mansueto 1 , George N. Naumov 1 , Ulrike Philippar 1 , Shruti Raut 1 , Peter Spacciapoli 1 , Dongyu Sun 1 , Phieng Siliphaivanh 1
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The ERK/MAPK pathway plays a central role in the regulation of critical cellular processes and is activated in more than 30% of human cancers. Specific BRAF and MEK inhibitors have shown clinical efficacy in patients for the treatment of BRAF-mutant melanoma. However, the majority of responses are transient, and resistance is often associated with pathway reactivation of the ERK signal pathway. Acquired resistance to these agents has led to greater interest in ERK, a downstream target of the MAPK pathway. De novo design efforts of a novel scaffold derived from SCH772984 by employing hydrogen bond interactions specific for ERK in the binding pocket identified 1-(1H-pyrazolo[4,3-c]pyridin-6-yl)ureas as a viable lead series. Sequential SAR studies led to the identification of highly potent and selective ERK inhibitors with low molecular weight and high LE. Compound 21 exhibited potent target engagement and strong tumor regression in the BRAFV600E xenograft model.
中文翻译：
发现细胞外信号调节激酶（ERK）的1-（1 H-吡唑并[4,3- c ]吡啶-6-基）脲抑制剂可治疗癌症
ERK / MAPK途径在关键细胞过程的调节中起着核心作用，并在30％以上的人类癌症中被激活。特定的BRAF和MEK抑制剂已在治疗BRAF突变型黑色素瘤的患者中显示出临床疗效。但是，大多数响应是瞬时的，耐药性通常与ERK信号通路的通路重新激活有关。对这些药物的获得性耐药已引起人们对ERK（MAPK途径的下游靶标）的更大兴趣。从头设计工作的新型支架从SCH772984通过在绑定袋中鉴定出1-（1 H -pyrazolo [4,3- c] pyridin-6-yl）ureas作为可行的先导系列。连续的SAR研究导致鉴定出具有低分子量和高LE的高效和选择性ERK抑制剂。在BRAF V600E异种移植模型中，化合物21表现出强大的靶标参与和强大的肿瘤消退能力。
更新日期：2016-07-01
中文翻译：
发现细胞外信号调节激酶（ERK）的1-（1 H-吡唑并[4,3- c ]吡啶-6-基）脲抑制剂可治疗癌症
ERK / MAPK途径在关键细胞过程的调节中起着核心作用，并在30％以上的人类癌症中被激活。特定的BRAF和MEK抑制剂已在治疗BRAF突变型黑色素瘤的患者中显示出临床疗效。但是，大多数响应是瞬时的，耐药性通常与ERK信号通路的通路重新激活有关。对这些药物的获得性耐药已引起人们对ERK（MAPK途径的下游靶标）的更大兴趣。从头设计工作的新型支架从SCH772984通过在绑定袋中鉴定出1-（1 H -pyrazolo [4,3- c] pyridin-6-yl）ureas作为可行的先导系列。连续的SAR研究导致鉴定出具有低分子量和高LE的高效和选择性ERK抑制剂。在BRAF V600E异种移植模型中，化合物21表现出强大的靶标参与和强大的肿瘤消退能力。
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