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Discovery of a Potent Nonpeptidomimetic, Small-Molecule Antagonist of Cellular Inhibitor of Apoptosis Protein 1 (cIAP1) and X-Linked Inhibitor of Apoptosis Protein (XIAP)
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2017-05-11 00:00:00 , DOI: 10.1021/acs.jmedchem.6b01877 Emiliano Tamanini 1 , Ildiko M. Buck 1 , Gianni Chessari 1 , Elisabetta Chiarparin 1 , James E. H. Day 1 , Martyn Frederickson 1 , Charlotte M. Griffiths-Jones 1 , Keisha Hearn 1 , Tom D. Heightman 1 , Aman Iqbal 1 , Christopher N. Johnson 1 , Edward J. Lewis 1 , Vanessa Martins 1 , Torren Peakman 1 , Michael Reader 1 , Sharna J. Rich 1 , George A. Ward 1 , Pamela A. Williams 1 , Nicola E. Wilsher 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2017-05-11 00:00:00 , DOI: 10.1021/acs.jmedchem.6b01877 Emiliano Tamanini 1 , Ildiko M. Buck 1 , Gianni Chessari 1 , Elisabetta Chiarparin 1 , James E. H. Day 1 , Martyn Frederickson 1 , Charlotte M. Griffiths-Jones 1 , Keisha Hearn 1 , Tom D. Heightman 1 , Aman Iqbal 1 , Christopher N. Johnson 1 , Edward J. Lewis 1 , Vanessa Martins 1 , Torren Peakman 1 , Michael Reader 1 , Sharna J. Rich 1 , George A. Ward 1 , Pamela A. Williams 1 , Nicola E. Wilsher 1
Affiliation
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XIAP and cIAP1 are members of the inhibitor of apoptosis protein (IAP) family and are key regulators of anti-apoptotic and pro-survival signaling pathways. Overexpression of IAPs occurs in various cancers and has been associated with tumor progression and resistance to treatment. Structure-based drug design (SBDD) guided by structural information from X-ray crystallography, computational studies, and NMR solution conformational analysis was successfully applied to a fragment-derived lead resulting in AT-IAP, a potent, orally bioavailable, dual antagonist of XIAP and cIAP1 and a structurally novel chemical probe for IAP biology.
中文翻译：
发现细胞凋亡蛋白1（cIAP1）和X连锁凋亡蛋白抑制剂（XIAP）的有效的非拟肽，小分子拮抗剂。
XIAP和cIAP1是凋亡蛋白（IAP）抑制剂家族的成员，并且是抗凋亡和促生存信号通路的关键调节剂。IAP的过度表达发生在各种癌症中，并且与肿瘤的进展和对治疗的抵抗力有关。基于X射线晶体学，计算研究和NMR溶液构象分析的结构信息指导的基于结构的药物设计（SBDD）已成功应用于片段衍生的铅，从而产生了AT-IAP，AT-IAP是一种有效的，口服生物利用型的双重拮抗剂XIAP和cIAP1以及用于IAP生物学的结构新颖的化学探针。
更新日期：2017-05-25
中文翻译：
发现细胞凋亡蛋白1（cIAP1）和X连锁凋亡蛋白抑制剂（XIAP）的有效的非拟肽，小分子拮抗剂。
XIAP和cIAP1是凋亡蛋白（IAP）抑制剂家族的成员，并且是抗凋亡和促生存信号通路的关键调节剂。IAP的过度表达发生在各种癌症中，并且与肿瘤的进展和对治疗的抵抗力有关。基于X射线晶体学，计算研究和NMR溶液构象分析的结构信息指导的基于结构的药物设计（SBDD）已成功应用于片段衍生的铅，从而产生了AT-IAP，AT-IAP是一种有效的，口服生物利用型的双重拮抗剂XIAP和cIAP1以及用于IAP生物学的结构新颖的化学探针。
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