Rapamycin vs TORin-1 or Gleevec vs Nilotinib: Simple chemical evolution that converts PAK1-blockers to TOR-blockers or vice versa?

IF 1.9 Q3 PHARMACOLOGY & PHARMACY Drug Discoveries and Therapeutics Pub Date : 2024-06-06 Epub Date: 2024-04-04 DOI:10.5582/ddt.2023.01097
Hiroshi Maruta, Hong He
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Abstract

Both PAK1 (RAC/CDC42-activating kinase 1) and TOR (Target of Rapamycin) are among the major oncogenic/ageing kinases. However, they play the opposite role in our immune system, namely immune system is suppressed by PAK1, while it requires TOR. Thus, PAK1-blockers, would be more effective for therapy of cancers, than TOR-blockers. Since 2015 when we discovered genetically that PDGF-induced melanogenesis depends on "PAK1", we are able to screening a series of PAK1-blockers as melanogenesis-inhibitors which could eventually promote longevity. Interestingly, rapamycin, the first TOR-inhibitor, promotes melanogenesis, clearly indicating that TOR suppresses melanogenesis. However, a new TOR-inhibitor called TORin-1 no longer suppresses immune system, and blocks melanogenesis in cell culture. These observations strongly indicate that TORin-1 acts as PAK1-blockers, instead of TOR-blockers, in vivo. Thus, it is most likely that melanogenesis in cell culture could enable us to discriminate PAK1-blockers from TORblockers.

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雷帕霉素与 TORin-1 或格列卫与尼罗替尼:将 PAK1 受体转换为 TOR 受体或反之亦然的简单化学进化?
PAK1(RAC/CDC42 激活激酶 1)和 TOR(雷帕霉素靶蛋白)都是主要的致癌/老化激酶。然而,它们在我们的免疫系统中却扮演着相反的角色,即免疫系统受到 PAK1 的抑制,而需要 TOR。因此,PAK1 受体阻断剂比 TOR 受体阻断剂更能有效治疗癌症。自2015年我们从基因上发现PDGF诱导的黑色素生成依赖于 "PAK1 "以来,我们能够筛选出一系列PAK1受体阻断剂,作为黑色素生成抑制剂,最终促进长寿。有趣的是,雷帕霉素作为第一种TOR抑制剂能促进黑色素生成,这清楚地表明TOR抑制了黑色素生成。然而,一种名为 TORin-1 的新型 TOR 抑制剂不再抑制免疫系统,而且还能阻止细胞培养中的黑色素生成。这些观察结果有力地表明,TORin-1 在体内的作用是 PAK1 受体阻断剂,而不是 TOR 受体阻断剂。因此,细胞培养中的黑色素生成极有可能使我们能够区分 PAK1 受体阻断剂和 TOR 受体阻断剂。
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来源期刊
Drug Discoveries and Therapeutics
Drug Discoveries and Therapeutics PHARMACOLOGY & PHARMACY-
CiteScore
3.20
自引率
3.20%
发文量
51
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