2. Academic Validation
  3. Identification of a novel potent CDK inhibitor degrading cyclinK with a superb activity to reverse trastuzumab-resistance in HER2-positive breast cancer in vivo

Identification of a novel potent CDK inhibitor degrading cyclinK with a superb activity to reverse trastuzumab-resistance in HER2-positive breast cancer in vivo

  • Eur J Med Chem. 2024 Jan 15:264:116014. doi: 10.1016/j.ejmech.2023.116014.
Ratnakar Reddy Kuchukulla 1,  Injeoung Hwang 2,  Suhn Hyung Kim 3,  Younghyeon Kye 1,  Narae Park 4,  Heary Cha 1,  Sojeong Moon 1,  Hwan Won Chung 5,  Cheolju Lee 6,  Gu Kong 7,  Wooyoung Hur 8
Affiliations

Affiliations

  • 1 HY-KIST Bioconvergence, Hanyang University, 222 Wangsimniro, Seongdong-gu, Seoul, 04763, Republic of Korea.
  • 2 HY-KIST Bioconvergence, Hanyang University, 222 Wangsimniro, Seongdong-gu, Seoul, 04763, Republic of Korea; Medicinal Materials Research Center, Korea Institute of Science and Technology (KIST), 5 Hwarangro 14 gil, Seongbuk-gu, Seoul, 02792, Republic of Korea.
  • 3 Medicinal Materials Research Center, Korea Institute of Science and Technology (KIST), 5 Hwarangro 14 gil, Seongbuk-gu, Seoul, 02792, Republic of Korea.
  • 4 Chemical & Biological Integrative Research Center, Korea Institute of Science and Technology (KIST), 5 Hwarangro 14 gil, Seongbuk-gu, Seoul, 02792, Republic of Korea; KHU-KIST Department of Converging Science and Technology, Kyung Hee University, 26 Kyungheedaero, Dongdaemun-gu, Seoul, 02447, Republic of Korea.
  • 5 Computational Science Research Center, Korea Institute of Science and Technology (KIST), 5 Hwarangro 14 gil, Seongbuk-gu, Seoul, 02792, Republic of Korea.
  • 6 Chemical & Biological Integrative Research Center, Korea Institute of Science and Technology (KIST), 5 Hwarangro 14 gil, Seongbuk-gu, Seoul, 02792, Republic of Korea.
  • 7 HY-KIST Bioconvergence, Hanyang University, 222 Wangsimniro, Seongdong-gu, Seoul, 04763, Republic of Korea; Medicinal Materials Research Center, Korea Institute of Science and Technology (KIST), 5 Hwarangro 14 gil, Seongbuk-gu, Seoul, 02792, Republic of Korea; Department of Pathology, Hanyang University College of Medicine, 222 Wangsimniro, Seongdong-gu, Seoul, 04763, Republic of Korea. Electronic address: gkong@hanyang.ac.kr.
  • 8 HY-KIST Bioconvergence, Hanyang University, 222 Wangsimniro, Seongdong-gu, Seoul, 04763, Republic of Korea; Medicinal Materials Research Center, Korea Institute of Science and Technology (KIST), 5 Hwarangro 14 gil, Seongbuk-gu, Seoul, 02792, Republic of Korea. Electronic address: whur@kist.re.kr.
PMID: 38061230 DOI: 10.1016/j.ejmech.2023.116014
Abstract

CDK12 is overexpressed in HER2-positive breast cancers and promotes tumorigenesis and trastuzumab resistance. Thus CDK12 is a good therapeutic target for the HER2-positive breast tumors resistant to trastuzumab. We previously reported a novel purine-based CDK Inhibitor with an ability to degrade cyclinK. Herein, we further explored and synthesized new derivatives, and identified a new potent pan-CDK inhibitor degrading cyclinK (32e). Compound 32e potently inhibited CDK12/cyclinK with IC50 = 3 nM, and suppressed the growth of the both trastuzumab-sensitive and trastuzumab-resistant HER2-positive breast Cancer cell lines (GI50's = 9-21 nM), which is superior to a potent, clinical pan-CDK inhibitor dinaciclib. Moreover, 32e (10, 20 mg/kg, ip, twice a week) showed a dose-dependent inhibition of tumor growth and a more dramatic anti-cancer effect than dinaciclib in mouse in vivo orthotopic breast Cancer model of trastuzumab-resistant HCC1954 cells. Kinome-wide inhibition profiling revealed that 32e at 1 μM exhibits a decent selectivity toward CDK-family kinases including CDK12 over Other wildtype protein kinases. Quantitative global proteomic analysis of 32e-treated HCC1954 cells demonstrated that 32e also showed a decent selectivity in degrading cyclinK over Other cyclins. Compound 32e could be developed as a drug for intractable trastuzumab-resistant HER2-positive breast cancers. Our current study would provide a useful insight in designing potent cyclinK degraders.

Keywords

CDK12 inhibitor; CyclinK degrader; Dinaciclib; HER2-positive breast cancer; Trastuzumab-resistance.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-157297
    CDK 抑制剂
    CDK
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