RIPK1,3 키나아제는 necroptosis 에서 중요한 역할을 하며, 과도한 necroptosis 는 면역질환과 염증질환을 유발할 수 있다. 이 연구의 목적은 선택적인 RIPK3 저해를 통해서 MLKL (Mixed lineage kinase domain-like) 인산화를 저해함으로써 necroptosis를 억제하는 것이다. 본 논문은 신규한 MLKL 인산화 저해제의 설계와 합성 그리고 ...
RIPK1,3 키나아제는 necroptosis 에서 중요한 역할을 하며, 과도한 necroptosis 는 면역질환과 염증질환을 유발할 수 있다. 이 연구의 목적은 선택적인 RIPK3 저해를 통해서 MLKL (Mixed lineage kinase domain-like) 인산화를 저해함으로써 necroptosis를 억제하는 것이다. 본 논문은 신규한 MLKL 인산화 저해제의 설계와 합성 그리고 SAR 토의를 포함한다. MLKL 인산화 저해제 탐색 목적으로 설계 합성한 37 종의 신규 유도체들 중에서, 대표 화합물인 16p의 pMLKL 저해 활성이 대조 약물인 GSK872의 활성과 동등 수준 이상으로 우수하다.
RIPK1,3 키나아제는 necroptosis 에서 중요한 역할을 하며, 과도한 necroptosis 는 면역질환과 염증질환을 유발할 수 있다. 이 연구의 목적은 선택적인 RIPK3 저해를 통해서 MLKL (Mixed lineage kinase domain-like) 인산화를 저해함으로써 necroptosis를 억제하는 것이다. 본 논문은 신규한 MLKL 인산화 저해제의 설계와 합성 그리고 SAR 토의를 포함한다. MLKL 인산화 저해제 탐색 목적으로 설계 합성한 37 종의 신규 유도체들 중에서, 대표 화합물인 16p의 pMLKL 저해 활성이 대조 약물인 GSK872의 활성과 동등 수준 이상으로 우수하다.
Necroptosis is one of the cell death phenomena. It damages cell tissues and causes various immune diseases. By those reasons, necroptosis has received an enormous attention in the development of therapeutic agents against immune and inflammation diseases. Necroptosis is caused by the action of RIPK1...
Necroptosis is one of the cell death phenomena. It damages cell tissues and causes various immune diseases. By those reasons, necroptosis has received an enormous attention in the development of therapeutic agents against immune and inflammation diseases. Necroptosis is caused by the action of RIPK1, RIPK3, and MLKL. Among them, we have focused on inhibition of pMLKL phosphorylated by RIPK3 kinase as pMLKL is necessary for necroptosis. In order to design and synthesize novel RIPK3 inhibitors, we adopted structural features of GSK872 known as a selective RIPK3 inhibitor. Potent and novel pMLKL inhibitors were rationally designed and synthesized for necroptosis targeted therapy. Structure-activity relationship (SAR) study of 37 novel derivatives aimed at inhibiting pMLKL was performed, and we found that (E)-N-(6-(4-chlorostyryl)pyrido[3,4-d]pyrimidin-4-yl)benzo[d]thiazol-5-amine (16p) possesses most potent inhibitory effects against necroptosis effect among the 37 derivatives.
Necroptosis is one of the cell death phenomena. It damages cell tissues and causes various immune diseases. By those reasons, necroptosis has received an enormous attention in the development of therapeutic agents against immune and inflammation diseases. Necroptosis is caused by the action of RIPK1, RIPK3, and MLKL. Among them, we have focused on inhibition of pMLKL phosphorylated by RIPK3 kinase as pMLKL is necessary for necroptosis. In order to design and synthesize novel RIPK3 inhibitors, we adopted structural features of GSK872 known as a selective RIPK3 inhibitor. Potent and novel pMLKL inhibitors were rationally designed and synthesized for necroptosis targeted therapy. Structure-activity relationship (SAR) study of 37 novel derivatives aimed at inhibiting pMLKL was performed, and we found that (E)-N-(6-(4-chlorostyryl)pyrido[3,4-d]pyrimidin-4-yl)benzo[d]thiazol-5-amine (16p) possesses most potent inhibitory effects against necroptosis effect among the 37 derivatives.
주제어
#pMLKL inhibitor Necroptosis RIPK3
학위논문 정보
저자
박찬중
학위수여기관
KU-KIST Graduate School of Converging Science and Technology, Korea University
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