Title |
CDKI-73: an orally bioavailable and highly efficacious CDK9 inhibitor against acute myeloid leukemia
|
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Published in |
Investigational New Drugs, September 2018
|
DOI | 10.1007/s10637-018-0661-2 |
Pubmed ID | |
Authors |
Muhammed H. Rahaman, Yingyi Yu, Longjin Zhong, Julian Adams, Frankie Lam, Peng Li, Ben Noll, Robert Milne, Jun Peng, Shudong Wang |
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. |
X Demographics
Geographical breakdown
Country | Count | As % |
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Australia | 1 | 33% |
Unknown | 2 | 67% |
Demographic breakdown
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Members of the public | 2 | 67% |
Scientists | 1 | 33% |
Mendeley readers
Geographical breakdown
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Demographic breakdown
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Student > Master | 5 | 20% |
Student > Bachelor | 4 | 16% |
Researcher | 3 | 12% |
Student > Ph. D. Student | 2 | 8% |
Student > Doctoral Student | 1 | 4% |
Other | 3 | 12% |
Unknown | 7 | 28% |
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Chemistry | 2 | 8% |
Medicine and Dentistry | 2 | 8% |
Other | 3 | 12% |
Unknown | 8 | 32% |