Novel 2,6,9-Trisubstituted Purines as Potent CDK Inhibitors Alleviating Trastuzumab-Resistance of HER2-Positive Breast Cancers
DC Field | Value | Language |
---|---|---|
dc.contributor.author | Kuchukulla, Ratnakar Reddy | - |
dc.contributor.author | Hwang, Injeoung | - |
dc.contributor.author | Park, Sang Won | - |
dc.contributor.author | Moon, Sojeong | - |
dc.contributor.author | Kim, Suhn Hyung | - |
dc.contributor.author | Kim, Sumin | - |
dc.contributor.author | Chung, Hwan Won | - |
dc.contributor.author | Ji, Mi-Jung | - |
dc.contributor.author | Park, Hyun-Mee | - |
dc.contributor.author | Kong, Gu | - |
dc.contributor.author | Hur, Wooyoung | - |
dc.date.accessioned | 2022-10-25T07:40:47Z | - |
dc.date.available | 2022-10-25T07:40:47Z | - |
dc.date.created | 2022-10-06 | - |
dc.date.issued | 2022-09 | - |
dc.identifier.issn | 1424-8247 | - |
dc.identifier.uri | https://scholarworks.bwise.kr/hanyang/handle/2021.sw.hanyang/172564 | - |
dc.description.abstract | HER2-positive (HER2+) breast cancer is defined by HER2 oncogene amplification on chromosome 17q12 and accounts for 15-20% population of breast-cancer patients. Therapeutic anti-HER2 antibody such as trastuzumab is used as the first-line therapy for HER2-positive breast cancers. However, more than 50% of the patients respond poorly to trastuzumab, illustrating that novel therapy is warranted to overcome the resistance. We previously reported that in the majority of HER2+ breast-cancer patients, CDK12 is co-amplified on 17q12 and involved in developing tumors and trastuzumab resistance, proposing CDK12 as a potential drug target for HER2+ breast cancers. Here, we designed and synthesized novel 2,6,9-trisubstituted purines as potent CDK12 inhibitors showing strong, equipotent antiproliferative activity against trastuzumab-sensitive HER2+ SK-Br3 cells and trastuzumab-resistant HER2+ HCC1954 cells (GI(50) values < 50 nM) both of which express a high level of CDK12. Two potent analogue 30d and 30e at 40, 200 nM greatly downregulated the levels of cyclinK and Pol II p-CTD (Ser2), as well as the expression of CDK12 downstream genes (IRS1 and WNT1) in a dose-dependent manner. We also observed structure-property relationship for a subset of potent analogues, and found that 30e is highly stable in liver microsomes with lack of CYP inhibition. In addition, 30d exhibited a synergy with trastuzumab in the both cells, suggesting that our inhibitors could be applied to alleviate trastuzumab-resistance of HER2+ breast cancers and escalate the efficacy of trastuzumab as well. Our study may provide insight into developing a novel therapy for HER2+ breast cancers. | - |
dc.language | 영어 | - |
dc.language.iso | en | - |
dc.publisher | MDPI | - |
dc.title | Novel 2,6,9-Trisubstituted Purines as Potent CDK Inhibitors Alleviating Trastuzumab-Resistance of HER2-Positive Breast Cancers | - |
dc.type | Article | - |
dc.contributor.affiliatedAuthor | Kong, Gu | - |
dc.identifier.doi | 10.3390/ph15091041 | - |
dc.identifier.scopusid | 2-s2.0-85138608739 | - |
dc.identifier.wosid | 000857018400001 | - |
dc.identifier.bibliographicCitation | PHARMACEUTICALS, v.15, no.9, pp.1 - 34 | - |
dc.relation.isPartOf | PHARMACEUTICALS | - |
dc.citation.title | PHARMACEUTICALS | - |
dc.citation.volume | 15 | - |
dc.citation.number | 9 | - |
dc.citation.startPage | 1 | - |
dc.citation.endPage | 34 | - |
dc.type.rims | ART | - |
dc.type.docType | Article | - |
dc.description.journalClass | 1 | - |
dc.description.isOpenAccess | Y | - |
dc.description.journalRegisteredClass | scie | - |
dc.description.journalRegisteredClass | scopus | - |
dc.relation.journalResearchArea | Pharmacology & Pharmacy | - |
dc.relation.journalWebOfScienceCategory | Chemistry, Medicinal | - |
dc.relation.journalWebOfScienceCategory | Pharmacology & Pharmacy | - |
dc.subject.keywordPlus | DINACICLIB SCH 727965 | - |
dc.subject.keywordPlus | HER2 | - |
dc.subject.keywordPlus | CHEMOTHERAPY | - |
dc.subject.keywordAuthor | HER2-positive breast cancer | - |
dc.subject.keywordAuthor | trastuzumab-resistance | - |
dc.subject.keywordAuthor | CDK12 inhibitor | - |
dc.subject.keywordAuthor | cyclinK degrader | - |
dc.subject.keywordAuthor | 2,6,9-trisubstituted purine | - |
dc.identifier.url | https://www.mdpi.com/1424-8247/15/9/1041 | - |
Items in ScholarWorks are protected by copyright, with all rights reserved, unless otherwise indicated.
222, Wangsimni-ro, Seongdong-gu, Seoul, 04763, Korea+82-2-2220-1365
COPYRIGHT © 2021 HANYANG UNIVERSITY.
Certain data included herein are derived from the © Web of Science of Clarivate Analytics. All rights reserved.
You may not copy or re-distribute this material in whole or in part without the prior written consent of Clarivate Analytics.