5JLJ

Crystal Structure of KPT8602 in complex with CRM1-Ran-RanBP1

5JLJ の概要

• エントリーDOI: 10.2210/pdb5jlj/pdb
• 分子名称: GTP-binding nuclear protein Ran, Ran-specific GTPase-activating protein 1, Exportin-1, ... (9 entities in total)
• 機能のキーワード: heat repeat, exportin-1, nuclear transport, transport receptor-inhibitor complex, protein transport
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 162225.08

構造登録者

Fung, H.Y.,Chook, Y.M. (登録日: 2016-04-27, 公開日: 2016-06-29, 最終更新日: 2023-09-27)

主引用文献

Hing, Z.A.,Fung, H.Y.,Ranganathan, P.,Mitchell, S.,El-Gamal, D.,Woyach, J.A.,Williams, K.,Goettl, V.M.,Smith, J.,Yu, X.,Meng, X.,Sun, Q.,Cagatay, T.,Lehman, A.M.,Lucas, D.M.,Baloglu, E.,Shacham, S.,Kauffman, M.G.,Byrd, J.C.,Chook, Y.M.,Garzon, R.,Lapalombella, R.
Next-generation XPO1 inhibitor shows improved efficacy and in vivo tolerability in hematological malignancies.
Leukemia, 30:2364-2372, 2016

PubMed Abstract: The nuclear export receptor, Exportin 1 (XPO1), mediates transport of growth-regulatory proteins, including tumor suppressors, and is overactive in many cancers, including chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML) and aggressive lymphomas. Oral selective inhibitor of nuclear export (SINE) compounds that block XPO1 function were recently identified and hold promise as a new therapeutic paradigm in many neoplasms. One of these compounds, KPT-330 (selinexor), has made progress in Phase I/II clinical trials, but systemic toxicities limit its administration to twice-per-week and requiring supportive care. We designed a new generation SINE compound, KPT-8602, with a similar mechanism of XPO1 inhibition and potency but considerably improved tolerability. Efficacy of KPT-8602 was evaluated in preclinical animal models of hematological malignancies, including CLL and AML. KPT-8602 shows similar in vitro potency compared with KPT-330 but lower central nervous system penetration, which resulted in enhanced tolerability, even when dosed daily, and improved survival in CLL and AML murine models compared with KPT-330. KPT-8602 is a promising compound for further development in hematological malignancies and other cancers in which upregulation of XPO1 is seen. The wider therapeutic window of KPT-8602 may also allow increased on-target efficacy leading to even more efficacious combinations with other targeted anticancer therapies.

PubMed: 27323910
DOI: 10.1038/leu.2016.136

実験手法

X-RAY DIFFRACTION (2.5 Å)