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Discovery of a novel CDK7 inhibitor YPN-005 in small cell lung cancer

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Abstract
In contrast to non-small cell lung cancer, there has been no significant progress in the development of therapies for the small cell lung cancer (SCLC) in recent decades. Although various targeted agents, including immunotherapies, have recently been developed for testing in clinical trials, novel therapeutic agents are still needed for SCLC. We developed a potent inhibitor of cyclin-dependent kinase 7 (CDK7), designated YPN-005, and sought to determine whether it showed any anticancer effects in SCLC cells, cisplatin or etoposide-resistant cells, or organoids derived from SCLC patients. In a panel of kinases assay, YPN-005 was highly selective for CDK7 and showed antiproliferative effects in SCLC and cells with acquired resistance to conventional anticancer drugs. Similar to other CDK7 inhibitors, YPN-005 treatment significantly decreased the phosphorylation of the carboxyl-terminal domain of RNA polymerase II. Consistent with the in vitro results, YPN-005 treatment showed a significant inhibition of tumor growth through the suppression of RNA polymerase II phosphorylation. Finally, YPN-005 showed potent anticancer effects in organoids derived from SCLC patients compared to another CDK7 inhibitor, THZ1. Therapeutic targeting of CDK7 in SCLC might be suitable for clinical investigation, and YPN-005 may be a promising therapeutic option for primary SCLC and SCLC with acquired resistance to conventional therapy.
Author(s)
최윤정이현정김다솜김동하강명희조용희최창민유자경이광옥최은경이재철노진경
Issued Date
2021
Type
Article
Keyword
CDK7 inhibitorResistanceSmall cell lung cancerTargeted therapy
DOI
10.1016/j.ejphar.2021.174298
URI
https://oak.ulsan.ac.kr/handle/2021.oak/9576
https://ulsan-primo.hosted.exlibrisgroup.com/primo-explore/fulldisplay?docid=TN_cdi_proquest_miscellaneous_2548909338&context=PC&vid=ULSAN&lang=ko_KR&search_scope=default_scope&adaptor=primo_central_multiple_fe&tab=default_tab&query=any,contains,Discovery%20of%20a%20novel%20CDK7%20inhibitor%20YPN-005%20in%20small%20cell%20lung%20cancer&offset=0&pcAvailability=true
Publisher
EUROPEAN JOURNAL OF PHARMACOLOGY
Location
네덜란드
Language
영어
ISSN
0014-2999
Citation Volume
907
Citation Number
0
Citation Start Page
0
Citation End Page
0
Appears in Collections:
Natural Science > Biological Sciences
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