Next-generation XPO1 inhibitor shows improved efficacy and in vivo tolerability in hematological malignancies

Z. A. Hing, H. Y.J. Fung, P. Ranganathan, S. Mitchell, Dalia A ElGamal, J. A. Woyach, K. Williams, V. M. Goettl, J. Smith, X. Yu, X. Meng, Q. Sun, T. Cagatay, A. M. Lehman, D. M. Lucas, E. Baloglu, S. Shacham, M. G. Kauffman, J. C. Byrd, Y. M. Chook & 2 others R. Garzon, R. Lapalombella

Research output: Contribution to journalArticle

29 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)2364-2372
Number of pages9
JournalLeukemia
Volume30
Issue number12
DOIs
StatePublished - Dec 1 2016
Externally publishedYes

Fingerprint

Hematologic Neoplasms
Cell Nucleus Active Transport
B-Cell Chronic Lymphocytic Leukemia
Acute Myeloid Leukemia
Tumor Suppressor Proteins
Neoplasms
Phase II Clinical Trials
Clinical Trials, Phase I
Cytoplasmic and Nuclear Receptors
Lymphoma
Up-Regulation
Therapeutics
Central Nervous System
Animal Models
KPT-330
Growth

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

Cite this

Hing, Z. A., Fung, H. Y. J., Ranganathan, P., Mitchell, S., ElGamal, D. A., Woyach, J. A., ... Lapalombella, R. (2016). Next-generation XPO1 inhibitor shows improved efficacy and in vivo tolerability in hematological malignancies. Leukemia, 30(12), 2364-2372. https://doi.org/10.1038/leu.2016.136

Next-generation XPO1 inhibitor shows improved efficacy and in vivo tolerability in hematological malignancies. / Hing, Z. A.; Fung, H. Y.J.; Ranganathan, P.; Mitchell, S.; ElGamal, Dalia A; 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.

In: Leukemia, Vol. 30, No. 12, 01.12.2016, p. 2364-2372.

Research output: Contribution to journalArticle

Hing, ZA, Fung, HYJ, Ranganathan, P, Mitchell, S, ElGamal, DA, Woyach, JA, Williams, K, Goettl, VM, Smith, J, Yu, X, Meng, X, Sun, Q, Cagatay, T, Lehman, AM, Lucas, DM, Baloglu, E, Shacham, S, Kauffman, MG, Byrd, JC, Chook, YM, Garzon, R & Lapalombella, R 2016, 'Next-generation XPO1 inhibitor shows improved efficacy and in vivo tolerability in hematological malignancies', Leukemia, vol. 30, no. 12, pp. 2364-2372. https://doi.org/10.1038/leu.2016.136
Hing, Z. A. ; Fung, H. Y.J. ; Ranganathan, P. ; Mitchell, S. ; ElGamal, Dalia A ; 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. In: Leukemia. 2016 ; Vol. 30, No. 12. pp. 2364-2372.
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