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Investigational New Drugs

, Volume 37, Issue 4, pp 625–635 | Cite as

CDKI-73: an orally bioavailable and highly efficacious CDK9 inhibitor against acute myeloid leukemia

  • Muhammed H. Rahaman
  • Yingyi Yu
  • Longjin Zhong
  • Julian Adams
  • Frankie Lam
  • Peng Li
  • Ben Noll
  • Robert Milne
  • Jun PengEmail author
  • Shudong WangEmail author
PRECLINICAL STUDIES

Summary

Acute myeloid leukemia (AML) is the most common form of acute leukemia with dismal long-term prognosis with age. The most aggressive subtype of AML is MLL-AML that is characterized by translocations of the mixed-lineage leukemia gene (MLL) and resistance to conventional chemotherapy. Cyclin dependent kinase 9 (CDK9) plays a crucial role in the MLL-driven oncogenic transcription, and hence, inhibiting activity of CDK9 has been proposed as a promising strategy for treatment of AML. We investigated the therapeutic potential of CDKI-73, one of the most potent CDK9 inhibitors, against a panel of AML cell lines and samples derived from 97 patients. CDKI-73 induced cancer cells undergoing apoptosis through transcriptional downregulation of anti-apoptotic proteins Bcl-2, Mcl-1 and XIAP by majorly targeting CDK9. Contrastively, it was relatively low toxic to the bone marrow cells of healthy donors. In MV4–11 xenograft mouse models, oral administration of CDKI-73 resulted in a marked inhibition of tumor growth (p < 0.0001) and prolongation of animal life span (P < 0.001) without causing body weight loss and other overt toxicities. The study suggests that CDKI-73 can be developed as a highly efficacious and orally deliverable therapeutic agent for treatment of AML.

Keywords

CDKI-73 CDK9 AML MLL-AML MV4–11 xenograft Apoptosis 

Notes

Acknowledgements

Muhammed H. Rahaman and Longjin Zhong acknowledge the support from the Australian Government Research Training Program Scholarship. We especially acknowledge the contribution of patients.

Funding

This work was partially supported by Channel 7 Children’s Research Foundation (Grant number 161300) and the Tour de Cure’s established Grant to SW.

Compliance with ethical standards

Conflicts of interest

The authors have no conflicts of interest.

Ethical approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted.

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

“Informed consent was obtained from all individual participants included in the study.”

Supplementary material

10637_2018_661_MOESM1_ESM.docx (40 kb)
ESM 1 (DOCX 40 kb)

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Centre for Drug Discovery and Development, School of Pharmacy and Medical Sciences, University of South Australia Cancer Research InstituteUniversity of South AustraliaAdelaideAustralia
  2. 2.Department of Haematology, Qilu HospitalShandong UniversityJinanPeople’s Republic of China

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