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

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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.

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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.

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Author notes

  1. Muhammed H. Rahaman, Yingyi Yu and Longjin Zhong contributed equally to this work.

Authors and Affiliations

  1. Centre for Drug Discovery and Development, School of Pharmacy and Medical Sciences, University of South Australia Cancer Research Institute, University of South Australia, Adelaide, Australia

    Muhammed H. Rahaman, Longjin Zhong, Julian Adams, Frankie Lam, Peng Li, Ben Noll, Robert Milne & Shudong Wang

  2. Department of Haematology, Qilu Hospital, Shandong University, Jinan, People’s Republic of China

    Yingyi Yu & Jun Peng

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  1. Muhammed H. Rahaman
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Correspondence to Jun Peng or Shudong Wang.

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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.

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Rahaman, M.H., Yu, Y., Zhong, L. et al. CDKI-73: an orally bioavailable and highly efficacious CDK9 inhibitor against acute myeloid leukemia. Invest New Drugs 37, 625–635 (2019). https://doi.org/10.1007/s10637-018-0661-2

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