Novel 2,6,9-Trisubstituted Purines as Potent CDK Inhibitors Alleviating Trastuzumab-Resistance of HER2-Positive Breast Cancersopen access
- Authors
- 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
- Issue Date
- Sep-2022
- Publisher
- MDPI
- Keywords
- HER2-positive breast cancer; trastuzumab-resistance; CDK12 inhibitor; cyclinK degrader; 2,6,9-trisubstituted purine
- Citation
- PHARMACEUTICALS, v.15, no.9, pp.1 - 34
- Indexed
- SCIE
SCOPUS
- Journal Title
- PHARMACEUTICALS
- Volume
- 15
- Number
- 9
- Start Page
- 1
- End Page
- 34
- URI
- https://scholarworks.bwise.kr/hanyang/handle/2021.sw.hanyang/172564
- DOI
- 10.3390/ph15091041
- ISSN
- 1424-8247
- 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.
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