2. Academic Validation
  3. CDKI-73: an orally bioavailable and highly efficacious CDK9 inhibitor against acute myeloid leukemia

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

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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