5JLJ

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

Summary for 5JLJ

• Entry DOI: 10.2210/pdb5jlj/pdb
• Descriptor: GTP-binding nuclear protein Ran, Ran-specific GTPase-activating protein 1, Exportin-1, ... (9 entities in total)
• Functional Keywords: heat repeat, exportin-1, nuclear transport, transport receptor-inhibitor complex, protein transport
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 3
• Total formula weight: 162225.08

Authors

Fung, H.Y.,Chook, Y.M. (deposition date: 2016-04-27, release date: 2016-06-29, Last modification date: 2023-09-27)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.5 Å)