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01-08-2019 | PRECLINICAL STUDIES

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

Authors: Muhammed H. Rahaman, Yingyi Yu, Longjin Zhong, Julian Adams, Frankie Lam, Peng Li, Ben Noll, Robert Milne, Jun Peng, Shudong Wang

Published in: Investigational New Drugs | Issue 4/2019

Summary

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.

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Title: CDKI-73: an orally bioavailable and highly efficacious CDK9 inhibitor against acute myeloid leukemia
Authors: Muhammed H. Rahaman
Yingyi Yu
Longjin Zhong
Julian Adams
Frankie Lam
Peng Li
Ben Noll
Robert Milne
Jun Peng
Shudong Wang
Publication date: 01-08-2019
Publisher: Springer US
Published in: Investigational New Drugs / Issue 4/2019
Print ISSN: 0167-6997
Electronic ISSN: 1573-0646
DOI: https://doi.org/10.1007/s10637-018-0661-2

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