Journal of Digital Convergence (디지털융복합연구)

The Society of Digital Policy and Management (한국디지털정책학회)
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Inhibitory Activities of Aryl-pyrazolopyrimidines targeting HIF-2𝛼

Aryl-pyrazolopyrimidine의 HIF-2𝛼 저해 활성

  • Hyosung Lee (Department of Pharmaceutical Science & Engineering)
  • 이효성 (서원대학교 제약공학과)
  • Received : 2024.11.16
  • Accepted : 2024.12.20
  • Published : 2024.12.28
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Abstract

HIF-2𝛼 is a transcription factor, playing a pivotal role in angiogenesis, and a valid target for drug design as reportedly revealed to play a crucial roles in pathophysiologic processes in various diseases. In this study, a chemical library has been investigated followed by structure-activity relationship study to discover an effective inhibitor targeting HIF-2𝛼. As an arylpyrazolopyrimidine exerted the inhibitory activity, a set of analogues were subjected to activity test for the further investigation. In order to test the inhibitory activity of each compound, HTB94 cells containing HRE-luciferase construct were infected HIF-2𝛼 by adenoviral infection and tested the luciferase activity in the presence of compounds. As a result, 2 arylpyrazolopyrimidines have been generated as HIF-2𝛼 inhibitors. This study was conducted by the convergence of chemistry and biology, and the resulting inhibitors may provide an useful tool for the related research and drug candidiates for the development of therapeutic agents.

HIF-2𝛼는 혈관생성에 중요한 역할을 하는 전사인자로 다양한 질환의 발병 기전에 중요한 역할을 하는 것이 밝혀져 약물설계의 유효한 표적이다. 본 연구에서는 화합물 라이브러리를 활성 기반으로 검색하여 유효한 활성을 나타내는 화합물을 선별하고 구조-활성 관계를 고려한 선택적 검색을 통하여 HIF-2𝛼의 저해제를 도출하고자 하였다. 화합물 라이브러리로부터 aryl-pyrazolopyrimidine의 저해 활성을 발견하였고 구조 기반의 유사 화합물들을 선별하여 HIF-2𝛼 저해 활성을 탐색하였다. HRE-luciferase를 도입하여 안정화한 HTB94 세포에 HIF-2𝛼 유전자를 adenovirus infection으로 도입하고 화합물을 처리하여 저해 활성을 측정하였다. 그 결과 2 종의 aryl-pyrazolopyridine이 HIF-2𝛼 저해제로 도출되었다. 본 연구는 화학과 생물학의 융복합 연구로 수행되었으며 결과물인 저해제는 HIF-2𝛼관련 연구에 도구로서 활용될 수 있고 관련 질환의 치료제 개발에도 기여할 수 있다.

Keywords

References

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