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dc.contributor.authorKuchukulla, Ratnakar Reddy-
dc.contributor.authorHwang, Injeoung-
dc.contributor.authorPark, Sang Won-
dc.contributor.authorMoon, Sojeong-
dc.contributor.authorKim, Suhn Hyung-
dc.contributor.authorKim, Sumin-
dc.contributor.authorChung, Hwan Won-
dc.contributor.authorJi, Mi-Jung-
dc.contributor.authorPark, Hyun-Mee-
dc.contributor.authorKong, Gu-
dc.contributor.authorHur, Wooyoung-
dc.date.accessioned2024-01-19T11:03:51Z-
dc.date.available2024-01-19T11:03:51Z-
dc.date.created2022-10-11-
dc.date.issued2022-09-
dc.identifier.issn1424-8247-
dc.identifier.urihttps://pubs.kist.re.kr/handle/201004/114575-
dc.description.abstractHER2-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.languageEnglish-
dc.publisherMultidisciplinary Digital Publishing Institute (MDPI)-
dc.titleNovel 2,6,9-Trisubstituted Purines as Potent CDK Inhibitors Alleviating Trastuzumab-Resistance of HER2-Positive Breast Cancers-
dc.typeArticle-
dc.identifier.doi10.3390/ph15091041-
dc.description.journalClass1-
dc.identifier.bibliographicCitationPharmaceuticals, v.15, no.9-
dc.citation.titlePharmaceuticals-
dc.citation.volume15-
dc.citation.number9-
dc.description.isOpenAccessY-
dc.description.journalRegisteredClassscie-
dc.description.journalRegisteredClassscopus-
dc.identifier.wosid000857018400001-
dc.relation.journalWebOfScienceCategoryChemistry, Medicinal-
dc.relation.journalWebOfScienceCategoryPharmacology & Pharmacy-
dc.relation.journalResearchAreaPharmacology & Pharmacy-
dc.type.docTypeArticle-
dc.subject.keywordPlusDINACICLIB SCH 727965-
dc.subject.keywordPlusHER2-
dc.subject.keywordPlusCHEMOTHERAPY-
dc.subject.keywordAuthorHER2-positive breast cancer-
dc.subject.keywordAuthortrastuzumab-resistance-
dc.subject.keywordAuthorCDK12 inhibitor-
dc.subject.keywordAuthorcyclinK degrader-
dc.subject.keywordAuthor2,6,9-trisubstituted purine-
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