Pharmaceutical composition comprising indolizine derivative for activating stimulator of interferon gene dependent signaling
- 주제(키워드) Cancer immunotherapy , Synergy drug , indolizine , stimulator of interferon gene
- 발행기관 아주대학교
- 지도교수 김은하
- 발행년도 2021
- 학위수여년월 2021. 2
- 학위명 석사
- 학과 및 전공 일반대학원 분자과학기술학과
- 실제URI http://www.dcollection.net/handler/ajou/000000030596
- 본문언어 영어
- 저작권 아주대학교 논문은 저작권에 의해 보호받습니다.
초록/요약
During the past few decades, cancer immunotherapy has emerged as a promising cancer treatment expected to overcome the limitations of conventional chemotherapy. Immune checkpoint inhibitors (ICIs) that block the interaction between receptors/ligands of major immune checkpoint molecules such as programmed cell death protein 1 (PD-1)/programmed cell death-ligand 1 (PD-L1) have attracted attention for their excellent and sustained clinical efficacy. However, there are limitations such as efficacy in the only subset of patients or carcinomas and resistance to treatment. In particular, cold tumors exhibiting a tumor microenvironment with immune-excluded or immune-desert phenotype have defects in the early stages of the immune cycle avoidance mechanism; hence, their responsiveness to ICIs is poor. Therefore, there is a need for innate immunity-inducing agents that increase the immune response by stimulating pattern recognition receptors such as stimulator of interferon genes (STING). The stimulator of interferon genes (STING) is an endoplasmic reticulum-localized adaptor that has been shown to be activated by natural cyclic dinucleotide (CDN) ligands, leading to STING dimerization, and downstream signaling to trigger innate immune gene transcription. Multiple reports demonstrated that activation of the STING protein by cyclic dinucleotide (CDN) trigger antitumor immunity. However, the inherent instability of CDN has limited current efforts. Herein, we developed a new synergy drug candidate for STING agonist, based on indolizine chemical core skeleton. The compound exhibited excellent efficacy for activating the STING signaling pathway without toxicity in combination with cGAMP, STING agonist. We envisioned the candidate could serve as a chemical tool to discover a new important regulator for the STING-mediated immunity.
more목차
1. Introduction 1
1.1. Recent trends in cancer treatment 1
1.2. Importance of innate immune activator 2
1.3. Stimulator of interferon genes (STING); target for innate immunity activators 3
1.4. STING agonists 5
1.5. Aim of thesis 6
2. Materials and methods 7
2.1. Materials and compound characterization 7
2.2. Synthetic procedure of indolizine derivatives 9
2.3. Analysis of STING activity for indolizine compounds 11
3. Results and discussions 14
3.1. Structure-Activity Relationship (SAR) study of Indolizine derivatives 14
3.2. Dose and STING-dependent response in ISRE assay for compound 42 17
3.3. In Vitro STING Signaling Pathway assay 18
4. Conclusion 23
5. References 24
