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Novel dual inhibitors targeting CDK4 and VEGFR2 synergistically suppressed cancer progression and angiogenesis.

Abstract：

:Based on the significantly synergistic effects of CDK4 and VEGFR2 inhibitors on growth of cancer cells, a series of novel multi-kinase inhibitors targeting CDK4 and VEGFR2 were designed, synthesized and evaluated, among which Roxyl-ZV-5J exhibited potent and balanced activities against both CDK4 and VEGFR2 with half-maximal inhibitory concentration at the nanomolar level. It effectively induced breast and cervical cancer cell cycle arrest and cell apoptosis. Roxyl-ZV-5J also inhibited the proliferation, tube formation and VEGFR2 downstream signaling pathways of HUVECs. Oral administration of Roxyl-ZV-5J led to significant tumor regression and anti-angiogenesis without obvious toxicity in SiHa xenograft mouse model. In addition, this compound showed good pharmacokinetics. This study confirmed a new tool for dual CDK-VEGFR2 pathways inhibition achieved with a single molecule, which provided valuable leads for further structural optimization and anti-angiogenesis and anti-tumor mechanism study.

journal_name

Eur J Med Chem

journal_title

European journal of medicinal chemistry

authors

Huang Z,Zhao B,Qin Z,Li Y,Wang T,Zhou W,Zheng J,Yang S,Shi Y,Fan Y,Xiang R

doi

10.1016/j.ejmech.2019.07.044

subject

Has Abstract

pub_date

2019-11-01 00:00:00

pages

111541

eissn

0223-5234

issn

1768-3254

pii

S0223-5234(19)30665-8

journal_volume

181

pub_type

杂志文章

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