Targeting human central nervous system protein kinases: An isoform selective p38αMAPK inhibitor that attenuates disease progression in Alzheimer's disease mouse models.
Targeting human central nervous system protein kinases: An isoform selective p38αMAPK inhibitor that attenuates disease progression in Alzheimer's disease mouse models.
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DOI：
10.1021/acschemneuro.5b00002
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发表时间：
2015-04-15
影响因子：
5
通讯作者：
Watterson, D. Martin
中科院分区：
文献类型：
--
作者：
Roy, Saktimayee M.;Grum-Tokars, Valerie L.;Schavocky, James P.;Saeed, Faisal;Staniszewski, Agnieszka;Teich, Andrew F.;Arancio, Ottavio;Bachstetter, Adam D.;Webster, Scott J.;Van Eldik, Linda J.;Minasov, George;Anderson, Wayne F.;Pelletier, Jeffrey C.;Watterson, D. Martin
关键词：
2001年首次批准的激酶抑制剂药物开启了用于肿瘤学适应症的酪氨酸激酶抑制剂药物的非凡十年，但丝氨酸/苏氨酸蛋白激酶抑制剂药物和中枢神经系统适应症仍然存在空白。由于应激蛋白参与了突触功能障碍和复杂疾病的易感性，因此在神经和神经精神疾病中具有特殊的意义。临床和临床前证据表明，应激相关激酶p38αMAPK是一种潜在的神经治疗靶点，但缺乏具有异构体选择性的p38αMAPK抑制剂候选者，而有望用于周围组织疾病适应症的混合激酶抑制剂药物在神经学适应症方面存在局限性。因此，对神经治疗假说的追求需要具有适当神经药理学特征的激酶异构体选择性抑制剂。突触功能障碍由于应激诱导神经元和神经胶质细胞中p38αMAPK的激活而提供了增强药理疗效的潜力，神经胶质细胞是突触病理生理轴的相互作用的细胞成分，将被调节。我们报道了一种新的异构体选择性p38MAPK抑制剂，MW01-18-150SRM(=MW150)，它能有效地抑制两种不同突触功能障碍小鼠的海马依赖联想记忆和空间记忆缺陷。提出了一种生物相容产品的合成方案，并从药物筛选中获得了阳性结果。P38αMAPK/MW150复合物的高分辨晶体结构证明了活性中心的结合，揭示了结合抑制剂的潜在低能构象，并对MW150‘MW150’MW150精致的靶向选择性提出了结构上的解释。据我们所知，MW150作为一种异构体选择性p38MAPK抑制剂或作为一种能够调节体内应激相关行为的激酶抑制剂是没有先例的。
The first kinase inhibitor drug approval in 2001 initiated a remarkable decade of tyrosine kinase inhibitor drugs for oncology indications, but a void exists for serine/threonine protein kinase inhibitor drugs and central nervous system indications. Stress kinases are of special interest in neurological and neuropsychiatric disorders due to their involvement in synaptic dysfunction and complex disease susceptibility. Clinical and preclinical evidence implicates the stress related kinase p38αMAPK as a potential neurotherapeutic target, but isoform selective p38αMAPK inhibitor candidates are lacking and the mixed kinase inhibitor drugs that are promising in peripheral tissue disease indications have limitations for neurologic indications. Therefore, pursuit of the neurotherapeutic hypothesis requires kinase isoform selective inhibitors with appropriate neuropharmacology features. Synaptic dysfunction disorders offer a potential for enhanced pharmacological efficacy due to stress-induced activation of p38αMAPK in both neurons and glia, the interacting cellular components of the synaptic pathophysiological axis, to be modulated. We report a novel isoform selective p38αMAPK inhibitor, MW01-18-150SRM (=MW150), that is efficacious in suppression of hippocampal-dependent associative and spatial memory deficits in two distinct synaptic dysfunction mouse models. A synthetic scheme for biocompatible product and positive outcomes from pharmacological screens are presented. The high-resolution crystallographic structure of the p38αMAPK/MW150 complex documents active site binding, reveals a potential low energy conformation of the bound inhibitor, and suggests a structural explanation for MW150’s exquisite target selectivity. As far as we are aware, MW150 is without precedent as an isoform selective p38MAPK inhibitor or as a kinase inhibitor capable of modulating in vivo stress related behavior.
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DOI：
10.1038/nrd2999
发表时间：
2009-11
期刊：
Nature reviews. Drug discovery
影响因子：
--
作者：
通讯作者：
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影响因子：
3.7
作者：
Morfini, Gerardo A.;Bosco, Daryl A.;Brady, Scott T.
通讯作者：
Brady, Scott T.
影响因子：
6.2
作者：
Bachstetter, Adam D.;Watterson, D. Martin;Van Eldik, Linda J.
通讯作者：
Van Eldik, Linda J.
影响因子：
3.7
作者：
Watterson, D. Martin;Grum-Tokars, Valerie L.;Van Eldik, Linda J.
通讯作者：
Van Eldik, Linda J.
DOI：
10.1007/978-3-7091-0932-8_24
发表时间：
2012-01-01
期刊：
SYNAPTIC PLASTICITY: DYNAMICS, DEVELOPMENT AND DISEASE
影响因子：
--
作者：
Picconi, Barbara;Piccoli, Giovanni;Calabresi, Paolo
通讯作者：
Calabresi, Paolo