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

Leukemia volume 30, pages 2364–2372 (2016)Cite this article

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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.

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Acknowledgements

We thank the patients who provided blood for the above-mentioned studies. We also thank Dr John B MacMillan, PhD, for thoughtful contributions to this manuscript. Results shown in this report are derived from work performed at Argonne National Laboratory, Structural Biology Center at the Advanced Photon Source. Argonne is operated by UChicago Argonne, LLC, for the US Department of Energy, Office of Biological and Environmental Research under contract DE-AC02-06CH11357. This work is funded by Cancer Prevention Research Institute of Texas (CPRIT) Grants RP120352 and RP150053 (to YMC), R01 GM069909 (to YMC), the University of Texas Southwestern Endowed Scholars Program (to YMC), Welch Foundation Grant I-1532 (to YMC), Leukemia and Lymphoma Society Scholar Award (to YMC), Croucher Foundation Scholarship (to HYJF), the Leukemia and Lymphoma Society in the form of a translational grant (to JCB and RL), K12 CA133250 (to JCB), R01CA192928 (to RL and JCB), R01CA188269 (to RG and JCB), F30CA196082 (to ZAH), the Department of Defense DOD W81XWH-14-01-0190 (to RL), the Leukemia and Lymphoma Society Special Fellow award (LLS 60046395 to PR) and the Leukemia and Lymphoma Society Scholar Award (LLS 20020030 to RG). This work was also supported by P30 CA016058.

Author contributions

ZAH, PR, HYJF, JCB, YMC, RG and RL designed the experiments, analyzed the data, wrote the paper and reviewed and approved the final version. EB designed KPT-8602. EB, SM, DE, KW, JAW, JS, XY, VMG, XM, QS, TC, DML, SS, MGK and AML planned and contributed to components of the experimental work presented (chemistry, biology, clinical or animal studies or statistical analysis of data), reviewed and modified versions of the paper and approved the final version.

Author information

Author notes

  1. Z A Hing, H Y J Fung and P Ranganathan: These authors contributed equally to this work.

  2. J C Byrd, Y M Chook, R Garzon and R Lapalombella: These senior authors contributed equally to this work.

Authors and Affiliations

  1. Medical Scientist Training Program, The Ohio State University, Columbus, OH, USA

    Z A Hing

  2. Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA

    Z A Hing, P Ranganathan, S Mitchell, D El-Gamal, J A Woyach, K Williams, V M Goettl, J Smith, X Yu, X Meng, D M Lucas, J C Byrd, R Garzon & R Lapalombella

  3. Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX, USA

    H Y J Fung, Q Sun, T Cagatay & Y M Chook

  4. The Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA

    P Ranganathan & R Garzon

  5. Center for Biostatistics, The Ohio State University, Columbus, OH, USA

    A M Lehman

  6. Karyopharm Therapeutics Inc., Newton, MA, USA

    E Baloglu, S Shacham & M G Kauffman

  7. Division of Medicinal Chemistry, College of Pharmacy, The Ohio State University, Columbus, OH, USA

    J C Byrd

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  1. Z A Hing
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Corresponding author

Correspondence to R Lapalombella.

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Competing interests

EB, SS and MGK are employees of Karyopharm Therapeutics Inc. and have financial interests in this company. YMC is a consultant for Karyopharm Therapeutics Inc. The other authors declare no conflict of interest.

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Hing, Z., Fung, H., Ranganathan, P. et al. Next-generation XPO1 inhibitor shows improved efficacy and in vivo tolerability in hematological malignancies. Leukemia 30, 2364–2372 (2016). https://doi.org/10.1038/leu.2016.136

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