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

  • Invest New Drugs. 2019 Aug;37(4):625-635. doi: 10.1007/s10637-018-0661-2.
Muhammed H Rahaman  1 ,  Yingyi Yu  2 ,  Longjin Zhong  1 ,  Julian Adams  1 ,  Frankie Lam  1 ,  Peng Li  1 ,  Ben Noll  1 ,  Robert Milne  1 ,  Jun Peng  3 ,  Shudong Wang  4
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.
  • 2. Department of Haematology, Qilu Hospital, Shandong University, Jinan, People's Republic of China.
  • 3. Department of Haematology, Qilu Hospital, Shandong University, Jinan, People's Republic of China. [email protected].
  • 4. 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. [email protected].
PMID: 30194564 DOI: 10.1007/s10637-018-0661-2
Abstract

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