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|Ref Type||Journal Article|
|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||Investigational new drugs|
|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.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|CDKI-73||CDK1 Inhibitor 13 CDK2 Inhibitor 18 CDK9 Inhibitor 16||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).|
|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|