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The identification and characterisation of autophagy inhibitors from the published kinase inhibitor sets.

来自已发表的激酶抑制剂组的自噬抑制剂的鉴定和表征。

  • 影响因子:4.05
  • DOI:10.1042/BCJ20190846
  • 作者列表:"Zachari M","Rainard JM","Pandarakalam GC","Robinson L","Gillespie J","Rajamanickam M","Hamon V","Morrison A","Ganley IG","McElroy SP
  • 发表时间:2020-02-28
Abstract

:Autophagy is a critical cellular homeostatic mechanism, the dysfunction of which has been linked to a wide variety of disease states. It is regulated through the activity of specific kinases, in particular Unc-51 like autophagy activating kinase 1 (ULK1) and Phosphatidylinositol 3-kinase vacuolar protein sorting 34 (VPS34), which have both been suggested as potential targets for drug development. To identify new chemical compounds that might provide useful chemical tools or act as starting points for drug development, we screened each protein against the Published Kinase Inhibitor Set (PKIS), a library of known kinase inhibitors. In vitro screening and analysis of the published selectivity profiles of the hits informed the selection of three relatively potent ATP-competitive inhibitors against each target that presented the least number of off-target kinases in common. Cellular assays confirmed potent inhibition of autophagy in response to two of the ULK1 inhibitors and all three of the VPS34 inhibitors. These compounds represent not only a new resource for the study of autophagy but also potential chemical starting points for the validation or invalidation of these two centrally important autophagy kinases in disease models.

摘要

: 自噬是一种关键的细胞稳态机制,其功能障碍与多种疾病状态有关。它通过特定激酶的活性调节,特别是Unc-51,如自噬激活激酶1 (ULK1) 和磷脂酰肌醇3-激酶液泡蛋白分选34 (VPS34),它们都被认为是药物开发的潜在靶标。为了鉴定可能提供有用的化学工具或作为药物开发起点的新化合物,我们针对已发表的激酶抑制剂集 (PKIS) (已知激酶抑制剂库) 筛选了每种蛋白。体外筛选和对已发表的命中选择性谱的分析告知针对每个靶标选择三种相对有效的ATP竞争性抑制剂,所述靶标呈现最少数量的共同脱靶激酶。细胞测定证实了对两种ULK1抑制剂和所有三种VPS34抑制剂的自噬的有效抑制。这些化合物不仅代表了自噬研究的新资源,也代表了在疾病模型中验证或无效这两种中心重要的自噬激酶的潜在化学起点。

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DOI:10.1259/bjr.20180883
作者列表:["Tran S","Puric E","Walser M","Poel R","Datta NR","Heuberger J","Pica A","Marder D","Lomax N","Bolsi A","Morach P","Bachtiary B","Seddon BM","Schneider R","Bodis S","Weber DC"]

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影响因子:1.41
发表时间:2020-03-01
DOI:10.1177/1078155219842277
作者列表:["Gyori DJ","Bullington SM","Crawford BS","Vernon VP"]

METHODS:BACKGROUND:National guidelines recommend screening and treatment for cancer-related bone disease and continued monitoring of bone-modifying agents. It is unclear whether a standardized screening tool is utilized to identify eligible patients and ensure appropriate supportive care is implemented. The purpose of this study was to evaluate current prescribing practices and optimize management of bone-modifying agents. METHODS:A retrospective chart review was performed to identify patients who received hormone deprivation therapy or had bone metastases through Hematology/Oncology or Urology clinics from 1 November 2016 to 31 October 2017. The primary endpoints of this study were the incidence of completed baseline dual-energy X-ray absorptiometry (DEXA) scan for patients on hormone deprivation therapy and percent of patients started on a bone-modifying agent for the prevention of skeletal-related events secondary to bone metastasis. Secondary endpoints included percent of patients with dental examinations prior to initiation, adequate calcium and vitamin D supplementation, incidence of osteonecrosis of the jaw or flu-like symptoms and education, and percent of bisphosphonate doses appropriately adjusted based on renal function. RESULTS:A total of 375 patients were assessed for baseline DEXA scans and bone-modifying therapy. Of the 226 patients on hormone deprivation therapy, 111 (49%) patients were appropriately screened with a DEXA scan prior to initiation of hormone deprivation therapy. Among the 149 patients with bone metastases, only 94 (63.1%) patients were started on a bone-modifying agent. CONCLUSIONS:Opportunities have been identified to optimize management of patients with cancer-related bone disease. Implementation of standardized tools may increase the rate of appropriate screening and initiation of bone-modifying therapy when warranted.

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影响因子:2.83
发表时间:2020-01-01
DOI:10.1007/s00520-019-04843-9
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