Antileukemic activity of YPN-005, a CDK7 inhibitor, inducing apoptosis through c-MYC and FLT3 suppression in acute myeloid leukemia

Koo, Bon-Kwan; Choi, Eun Ji; Hur, Eun-Hye; Moon, Ju Hyun; Kim, Ji Yun; Park, Han‐Seung; Choi, Yun Suk; Lee, Jung‐Hee; Lee, Kyoo‐Hyung; Choi, Eun Kyung; Kim, Jinhwan; Lee, Je‐Hwan

doi:10.1016/j.heliyon.2022.e11004

Cited by 6 publications

(1 citation statement)

References 27 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Recently, other CDK7 inhibitors have been introduced, some of which have already entered clinical trials, namely, LY3405105, Q901 and XL102. Nevertheless, limited information about their mode of action, kinase selectivity or structure has been disclosed [19][20][21][22][23]. We have previously reported several series of potent 3,5,7-trisubstitued pyrazolo [4,3d]pyrimidine CDK inhibitors with strong anticancer activity in vitro and in vivo [24][25][26][27].…”

Section: Introductionmentioning

confidence: 99%

Characterization of new highly selective pyrazolo[4,3-d]pyrimidine inhibitor of CDK7

Kovalová

Havlı́cěk

Djukic

et al. 2023

Preprint

View full text Add to dashboard Cite

Targeting cyclin-dependent kinase 7 (CDK7) provides an interesting therapeutic option in cancer therapy because this kinase participates in regulating the cell cycle and transcription. Here, we describe a new trisubstituted pyrazolo[4,3-d]pyrimidine derivative, LGR6768, that inhibits CDK7 in the nanomolar range and displays favourable selectivity across the CDK family. We determined the structure of fully active CDK2/cyclin A2 in complex with LGR6768 at 2.6 angstrom resolution using X-ray crystallography, revealing conserved interactions within the active site. Structural analysis and comparison with LGR6768 docked to CDK7 provides an explanation of the observed biochemical selectivity, which is linked to a conformational difference in the biphenyl moiety. In cellular experiments, LGR6768 affected regulation of the cell cycle and transcription by inhibiting the phosphorylation of cell cycle CDKs and the carboxy-terminal domain of RNA polymerase II, respectively. LGR6768 limited the proliferation of several leukaemia cell lines, triggered significant changes in protein and mRNA levels related to CDK7 inhibition and induced apoptosis in dose- and time-dependent experiments. Our work supports previous findings and provides further information for the development of selective CDK7 inhibitors.

show abstract