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

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.

• Authors: Muhammed H Rahaman, Yingyi Yu, Longjin Zhong, Julian Adams, Frankie Lam, Peng Li, Ben Noll, Robert Milne, Jun Peng, Shudong Wang
• Journal: Investigational new drugs (Invest New Drugs) Vol. 37 Issue 4 Pg. 625-635 (08 2019) ISSN: 1573-0646 [Electronic] United States
• PMID: 30194564 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 3-(5-fluoro-4-(4-methyl-2-(methylamino)thiazol-5-yl)pyrimidin-2-ylamino)benzenesulfonamide
• Antineoplastic Agents
• Apoptosis Regulatory Proteins
• Protein Kinase Inhibitors
• Pyrimidines
• Sulfonamides
• CDK9 protein, human
• Cyclin-Dependent Kinase 9

Topics

• Administration, Oral
• Adult
• Animals
• Antineoplastic Agents (pharmacokinetics, pharmacology, therapeutic use)
• Apoptosis (drug effects)
• Apoptosis Regulatory Proteins (genetics, metabolism)
• Biological Availability
• Bone Marrow Cells (drug effects)
• Cell Line, Tumor
• Cyclin-Dependent Kinase 9 (antagonists & inhibitors)
• Female
• Humans
• Leukemia, Myeloid, Acute (drug therapy, genetics, metabolism, pathology)
• Male
• Mice, Inbred BALB C
• Mice, Nude
• Middle Aged
• Protein Kinase Inhibitors (pharmacokinetics, pharmacology, therapeutic use)
• Pyrimidines (pharmacokinetics, pharmacology, therapeutic use)
• Sulfonamides (pharmacokinetics, pharmacology, therapeutic use)
• Tumor Burden (drug effects)