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您的检索式：作者名="Kyle Vaughn Laster"
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| 1 | Novel dual inhibitor for targeting PIM1 and FGFR1 kinases inhibits colorectal cancer growth in vitro and patient-derived xenografts in vivo显示文摘Colorectal cancer(CRC) is the second most common cause of cancer-related death in the world. The pro-viral integration site for Moloney murine leukemia virus 1(PIM1) is a proto-oncogene and belongs to the serine/threonine kinase family, which are involved in cell proliferation, migration,and apoptosis. Fibroblast growth factor receptor 1(FGFR1) is a tyrosine kinase that has been implicated in cell proliferation, differentiation and migration. Small molecule HCI-48 is a derivative of chalcone, a class of compounds known to possess anti-tumor, anti-inflammatory and antibacterial effects. However,the underlying mechanism of chalcones against colorectal cancer remains unclear. This study reports that HCI-48 mainly targets PIM1 and FGFR1 kinases, thereby eliciting antitumor effects on colorectal cancer growth in vitro and in vivo. HCI-48 inhibited the activity of both PIM1 and FGFR1 kinases in an ATPdependent manner, as revealed by computational docking models. Cell-based assays showed that HCI-48inhibited cell proliferation in CRC cells(HCT-15, DLD1, HCT-116 and SW620), and induced cell cycle arrest in the G2/M phase through modulation of cyclin A2. HCI-48 also induced cellular apoptosis, as evidenced by an increase in the expression of apoptosis biomarkers such as cleaved PARP, cleaved caspase 3 and cleaved caspase 7. Moreover, HCI-48 attenuated the activation of downstream components of the PIM1 and FGFR1 signaling pathways. Using patient-derived xenograft(PDX) murine tumor models,we found that treatment with HCI-48 diminished the PDX tumor growth of implanted CRC tissue expressing high protein levels of PIM1 and FGFR1. This study suggests that the inhibitory effect of HCI-48 on colorectal tumor growth is mainly mediated through the dual-targeting of PIM1 and FGFR1kinases. This work provides a theoretical basis for the future application of HCI-48 in the treatment of clinical CRC. | Fanxiang Yin Ran Zhao Dhilli Rao Gorja Xiaorong Fu Ning Lu Hai Huang Beibei Xu Hanyong Chen Jung-Hyun Shim Kangdong Liu Zhi Li Kyle Vaughn Laster Zigang Dong Mee-Hyun Lee | 2022 | Acta Pharmaceutica Sinica B2022，12，11： | 1 |
| 2 | Cdc2-like kinases:structure,biological function,and therapeutic targets for diseases显示文摘The CLKs(Cdc2-like kinases)belong to the dual-specificity protein kinase family and play crucial roles in regulating transcript splicing via the phosphorylation of SR proteins(SRSF1–12),catalyzing spliceosome molecular machinery,and modulating the activities or expression of non-splicing proteins.The dysregulation of these processes is linked with various diseases,including neurodegenerative diseases,Duchenne muscular dystrophy,inflammatory diseases,viral replication,and cancer.Thus,CLKs have been considered as potential therapeutic targets,and significant efforts have been exerted to discover potent CLKs inhibitors.In particular,clinical trials aiming to assess the activities of the small molecules Lorecivivint on knee Osteoarthritis patients,and Cirtuvivint and Silmitasertib in different advanced tumors have been investigated for therapeutic usage.In this review,we comprehensively documented the structure and biological functions of CLKs in various human diseases and summarized the significance of related inhibitors in therapeutics.Our discussion highlights the most recent CLKs research,paving the way for the clinical treatment of various human diseases. | Mengqiu Song Luping Pang Mengmeng Zhang Yingzi Qu Kyle Vaughn Laster Zigang Dong | 2023 | Signal Transduction and Targeted Therapy2023，8，5： | 0 |
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