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Pre-clinical Evaluation of Tyrosine Kinase Inhibitors for Treatment of Acute Leukemia
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CDKI-73: an orally bioavailable and highly efficacious CDK9 inhibitor against acute myeloid leukemia

Muhammed H Rahaman1, Yingyi Yu2, Longjin Zhong1

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

Investigational New Drugs
|September 9, 2018
PubMed

Insights

CDKI-73, a potent cyclin-dependent kinase 9 (CDK9) inhibitor, effectively treats acute myeloid leukemia (AML) by inducing cancer cell apoptosis. This oral therapeutic shows promise with low toxicity in preclinical models.

Area of Science:

  • Hematology
  • Oncology
  • Molecular Biology

Background:

  • Acute myeloid leukemia (AML) is a common hematologic malignancy with poor prognosis, particularly MLL-AML subtypes.
  • Mixed-lineage leukemia gene (MLL) translocations drive aggressive AML, conferring resistance to standard chemotherapy.
  • Cyclin-dependent kinase 9 (CDK9) is critical for MLL-driven oncogenic transcription, making it a therapeutic target.

Purpose of the Study:

  • To evaluate the therapeutic efficacy of CDKI-73, a potent CDK9 inhibitor, in preclinical models of AML.
  • To investigate the mechanism of action of CDKI-73 in AML cells.
  • To assess the safety and tolerability of CDKI-73 in vivo.

Main Methods:

  • Treatment of AML cell lines and patient-derived samples with CDKI-73.
  • Analysis of apoptosis induction and protein expression (Bcl-2, Mcl-1, XIAP).
  • Assessment of CDKI-73 toxicity in healthy donor bone marrow cells.
  • Evaluation of CDKI-73 efficacy in MV4-11 xenograft mouse models.

Main Results:

  • CDKI-73 induced apoptosis in AML cells by downregulating anti-apoptotic proteins, primarily via CDK9 inhibition.
  • The compound exhibited low toxicity towards healthy bone marrow cells.
  • Oral administration of CDKI-73 significantly inhibited tumor growth and prolonged survival in mice without overt toxicity.

Conclusions:

  • CDKI-73 demonstrates significant anti-leukemic activity against AML.
  • Targeting CDK9 with CDKI-73 represents a promising therapeutic strategy for AML.
  • CDKI-73 is a potential orally deliverable agent for AML treatment.
Keywords:
AMLApoptosisCDK9CDKI-73MLL-AMLMV4–11 xenograft

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