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Novel 2,6,9-Trisubstituted Purines as Potent CDK Inhibitors Alleviating Trastuzumab-Resistance of HER2-Positive Breast Cancers

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...

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Autores principales: Kuchukulla, Ratnakar Reddy, Hwang, Injeoung, Park, Sang Won, Moon, Sojeong, Kim, Suhn Hyung, Kim, Sumin, Chung, Hwan Won, Ji, Mi-Jung, Park, Hyun-Mee, Kong, Gu, Hur, Wooyoung
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9506414/
https://www.ncbi.nlm.nih.gov/pubmed/36145262
http://dx.doi.org/10.3390/ph15091041
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author Kuchukulla, Ratnakar Reddy
Hwang, Injeoung
Park, Sang Won
Moon, Sojeong
Kim, Suhn Hyung
Kim, Sumin
Chung, Hwan Won
Ji, Mi-Jung
Park, Hyun-Mee
Kong, Gu
Hur, Wooyoung
author_facet Kuchukulla, Ratnakar Reddy
Hwang, Injeoung
Park, Sang Won
Moon, Sojeong
Kim, Suhn Hyung
Kim, Sumin
Chung, Hwan Won
Ji, Mi-Jung
Park, Hyun-Mee
Kong, Gu
Hur, Wooyoung
author_sort Kuchukulla, Ratnakar Reddy
collection PubMed
description 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.
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spelling pubmed-95064142022-09-24 Novel 2,6,9-Trisubstituted Purines as Potent CDK Inhibitors Alleviating Trastuzumab-Resistance of HER2-Positive Breast Cancers Kuchukulla, Ratnakar Reddy Hwang, Injeoung Park, Sang Won Moon, Sojeong Kim, Suhn Hyung Kim, Sumin Chung, Hwan Won Ji, Mi-Jung Park, Hyun-Mee Kong, Gu Hur, Wooyoung Pharmaceuticals (Basel) Article 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. MDPI 2022-08-23 /pmc/articles/PMC9506414/ /pubmed/36145262 http://dx.doi.org/10.3390/ph15091041 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Kuchukulla, Ratnakar Reddy
Hwang, Injeoung
Park, Sang Won
Moon, Sojeong
Kim, Suhn Hyung
Kim, Sumin
Chung, Hwan Won
Ji, Mi-Jung
Park, Hyun-Mee
Kong, Gu
Hur, Wooyoung
Novel 2,6,9-Trisubstituted Purines as Potent CDK Inhibitors Alleviating Trastuzumab-Resistance of HER2-Positive Breast Cancers
title Novel 2,6,9-Trisubstituted Purines as Potent CDK Inhibitors Alleviating Trastuzumab-Resistance of HER2-Positive Breast Cancers
title_full Novel 2,6,9-Trisubstituted Purines as Potent CDK Inhibitors Alleviating Trastuzumab-Resistance of HER2-Positive Breast Cancers
title_fullStr Novel 2,6,9-Trisubstituted Purines as Potent CDK Inhibitors Alleviating Trastuzumab-Resistance of HER2-Positive Breast Cancers
title_full_unstemmed Novel 2,6,9-Trisubstituted Purines as Potent CDK Inhibitors Alleviating Trastuzumab-Resistance of HER2-Positive Breast Cancers
title_short Novel 2,6,9-Trisubstituted Purines as Potent CDK Inhibitors Alleviating Trastuzumab-Resistance of HER2-Positive Breast Cancers
title_sort novel 2,6,9-trisubstituted purines as potent cdk inhibitors alleviating trastuzumab-resistance of her2-positive breast cancers
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9506414/
https://www.ncbi.nlm.nih.gov/pubmed/36145262
http://dx.doi.org/10.3390/ph15091041
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