Next-generation XPO1 inhibitor shows improved efficacy and in vivo tolerability in hematological malignancies.
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.
Medical Scientist Training Program, The Ohio State University, Columbus, OH, USA.|Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.
Z A
ZA
Hing
Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
H Y J
HY
Fung
Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.|The Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
P
P
Ranganathan
Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.
S
S
Mitchell
Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.
D
D
El-Gamal
Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.
J A
JA
Woyach
Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.
K
K
Williams
Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.
V M
VM
Goettl
Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.
J
J
Smith
Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.
X
X
Yu
Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.
X
X
Meng
Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Q
Q
Sun
Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
T
T
Cagatay
Center for Biostatistics, The Ohio State University, Columbus, OH, USA.
A M
AM
Lehman
Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.
D M
DM
Lucas
Karyopharm Therapeutics Inc., Newton, MA, USA.
E
E
Baloglu
Karyopharm Therapeutics Inc., Newton, MA, USA.
S
S
Shacham
Karyopharm Therapeutics Inc., Newton, MA, USA.
M G
MG
Kauffman
Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.|Division of Medicinal Chemistry, College of Pharmacy, The Ohio State University, Columbus, OH, USA.
J C
JC
Byrd
Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Y M
YM
Chook
Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.|The Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
R
R
Garzon
Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.
R
R
Lapalombella
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D019337:Hematologic Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D064593:Heterografts; D006801:Humans; D028884:Karyopherins / Q000037:antagonists & inhibitors*; D051379:Mice; D009361:Neoplasm Invasiveness; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors*; D015996:Survival Rate; D016896:Treatment Outcome; D000097606:Exportin 1 Protein
D000970:Antineoplastic Agents; D028884:Karyopherins; D018160:Receptors, Cytoplasmic and Nuclear; D000097606:Exportin 1 Protein