KIRA8 | 1630086-20-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 英文名称: KIRA8
• 英文别名: AMG-18；(S)-2-Chloro-N-(6-methyl-5-((3-(2-(piperidin-3-ylamino)pyrimidin-4-yl)pyridin-2-yl)oxy)naphthalen-1-yl)benzenesulfonamide；2-chloro-N-[6-methyl-5-[3-[2-[[(3S)-piperidin-3-yl]amino]pyrimidin-4-yl]pyridin-2-yl]oxynaphthalen-1-yl]benzenesulfonamide
• CAS: 1630086-20-2
• 化学式: C₃₁H₂₉ClN₆O₃S
• 分子量: 601.129
• InChiKey: XMWUCMFVDXDRDE-NRFANRHFSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.9
• 重原子数：
  42
• 可旋转键数：
  8
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.19
• 拓扑面积：
  127
• 氢给体数：
  3
• 氢受体数：
  9

安全信息

• 危险性防范说明：
  P261,P305+P351+P338
• 危险性描述：
  H302,H315,H319,H335

反应信息

• 作为产物：
  描述：

  (S)-tert-butyl 3-((4-(2-((5-(2-chlorophenylsulfonamido)-2-methylnaphthalen-1-yl)oxy)pyridin-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate 在 三氟乙酸 作用下， 以 二氯甲烷 为溶剂， 反应 0.25h， 以92%的产率得到KIRA8
  参考文献：
  名称：

  Unfolded Protein Response in Cancer: IRE1α Inhibition by Selective Kinase Ligands Does Not Impair Tumor Cell Viability

  摘要：

  The kinase/endonuclease inositol requiring enzyme 1 (IRE1 alpha), one of the sensors of unfolded protein accumulation in the endoplasmic reticulum that triggers the unfolded protein response (UPR), has been investigated as an anticancer target. We identified potent allosteric inhibitors of IRE1 alpha endonuclease activity that bound to the kinase site on the enzyme. Structure-activity relationship (SAR) studies led to 16 and 18, which were selective in kinase screens and were potent against recombinant IRE1 alpha endonuclease as well as cellular IRE1 alpha. The first X-ray crystal structure of a kinase inhibitor (16) bound to hIRE1 alpha was obtained. Screening of native tumor cell lines (>300) against selective IRE1 alpha inhibitors failed to demonstrate any effect on cellular viability. These results suggest that IRE1 alpha activity is not essential for viability in most tumor cell lines, in vitro, and that interfering with the survival functions of the UPR may not be an effective strategy to block tumorigenesis.

  DOI：

  10.1021/ml500315b

文献信息

• Development of a Chemical Toolset for Studying the Paralog-Specific Function of IRE1
  作者：Hannah C. Feldman、Venkata Narayana Vidadala、Zachary E. Potter、Feroz R. Papa、Bradley J. Backes、Dustin J. Maly

  DOI：10.1021/acschembio.9b00482

  日期：2019.12.20

  The dual kinase endoribonuclease IRE1 is a master regulator of cell fate decisions in cells experiencing endoplasmic reticulum (ER) stress. In mammalian cells, there are two paralogs of IRE1: IRE1 alpha and IRE1 beta. While IRE1 alpha has been extensively studied, much less is understood about IRE1 beta and its role in signaling. In addition, whether the regulation of IRE1 beta's enzymatic activities varies compared to IRE1 alpha is not known. Here, we show that the RNase domain of IRE1 beta is enzymatically active and capable of cleaving an XBP1 RNA mini-substrate in vitro. Using ATP-competitive inhibitors, we find that, like IRE1 alpha, there is an allosteric relationship between the kinase and RNase domains of IRE1 beta. This allowed us to develop a novel toolset of both paralog specific and dual-IRE1 alpha/beta kinase inhibitors that attenuate RNase activity (KIRAs). Using sequence alignments of IRE1 alpha and IRE1 beta, we propose a model for paralog-selective inhibition through interactions with nonconserved residues that differentiate the ATP-binding pockets of IRE1 alpha and IRE1 beta.
• METHODS FOR CONTROLLING PROSTAGLANDIN-MEDIATED BIOLOGICAL PROCESSES
  申请人：Cornell University

  公开号：US20220160705A1

  公开（公告）日：2022-05-26

  Described herein are compositions and methods for reducing prostaglandin production and pain in a mammalian or avian subject. Such compositions and methods inhibit reduce prostaglandinendoperoxide synthase 2 (Ptgs2/Cox-2) and prostaglandin E synthase (Ptges/mPGES-1) activities in the subject, but do not substantially inhibit prostaglandin-endoperoxide synthase 1 (Cox1) or prostaglandin E synthase 2 activities in the subject.