Reference Detail

Ref Type

Journal Article

PMID

(30194564)

Authors

Rahaman MH, Yu Y, Zhong L, Adams J, Lam F, Li P, Noll B, Milne R, Peng J, Wang S

Title

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

Journal	Vol	Issue	Date	Pages	Journal Short Title
Investigational new drugs	37	4	2019 08	625-635	Invest New Drugs

URL

Abstract Text

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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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
CDKI-73	CDKI-73	1	0

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
CDKI-73			CDK1 Inhibitor 13 CDK2 Inhibitor 31 CDK9 Inhibitor 21	CDKI-73 is a kinase inhibitor that blocks CDK9, CDK1, and CDK2 activity, which may lead to apoptotic activity and inhibition of cell proliferation and tumor growth (PMID: 30194564, PMID: 24495868, PMID: 32368391).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
KMT2A fusion	acute myeloid leukemia	sensitive	CDKI-73	Preclinical - Cell line xenograft	Actionable	In a preclinical study, CDKI-73 treatment inhibited Cdk9 kinase activity and viability, and induced apoptosis in acute myeloid leukemia cell lines harboring KMT2A fusions in culture, and inhibited tumor growth and induced regression in a cell line xenograft model (PMID: 30194564).	30194564