Snythesis and biological evaluation of thiazolopyridine derivatives as c-KIT inhibitors

다국어 초록 (Multilingual Abstract)

c-KIT, which a type III receptor tyrosine kinase(RTK), has dysfunction signaling, result in tumorigenesis. More than 90% of gastrointestinal stromal tumor (GIST) involves c-KIT activating mutants which have been used as a diagnostic indicator of GIST. In this study, a selective and potent c-KIT inhibitor was rationally designed for GIST targeted therapy. Structure-activity relationship (SAR) study of 25 derivatives against c-KIT was conducted and N-(3-(2-aminothiazolo[5,4-b]pyridin-6-yl)-4-methylphenyl)-4-((4 methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)benzamide (7s) showed most potent inhibitory effect against c-KIT. 7s is comparable to imatinib in terms of enzymatic activity against c-KIT WT and anti-proliferative activity on GIST-T1 cells. 7s possesses great kinase selectivity against a panel of 371 kinases. It is worth noting that 7s exhibits a 10 fold higher anti-proliferative activity than imatinib on imatinib-resistant HMC (Human Mast Cell) 1.2. cells harboring both c-KIT-D816V and c-KIT-V560G. Molecular docking study reveals that H-bonding interaction between aminothiazole moiety of 7s and c-KIT-Cys673. Taken together, this study suggests that 7s could be a lead compound to override imatinib-resistant GIST.

국문 초록 (Abstract)

위장관기질종양(GIST)의 90% 이상이 c-KIT 활성화 돌연변이종 (activating mutants)에 의해 발병되며 이는 GIST의 진단에 지표로 사용된다. 이 연구의 목적은 GIST를 타겟으로 하는 선택적이고 활성이 우수한 c-KIT 억제제를 합리적으로 설계하여 합성하였다. 대표화합물인 7s는 c-KIT WT에 대한 효소활성 및 GIST-T1 세포주에 대한 항 증식 활성이 이마티닙과 상응한다. 7s는 371개의 키나아제들 중에서 c-KIT에 대해 우수한 키나아제 선택성을 나타낸다. 주목할만한 점은 c-KIT-D816V 및 c-KIT-V560G 돌연변이를 갖는 이마티닙-내성을 갖는 HMC1.2 세포주에서 7s가 imatinib보다 10배 높은 항 증식 활성을 나타낸다. 분자 도킹(docking) 연구는 7의 아미노싸이아졸(aminothiazole) 부분과 c-KIT의 Cys673과의 수소결합 상호작용을 나타낸다. 종합적으로, 이 연구는 7s가 이마티닙 내성 GIST를 대체하는 주요 화합물일 수 있음을 제안한다.

목차 (Table of Contents)

• Table of contents
• Introduction 1
• Results and Discussion 5
• 1. Synthesis of c-KIT inhibitor derivatives 5
• 1.1 Synthesis of intermediate compound, 3b 7
• 1.2 Synthesis of intermediate compound, 3e 7
• 1.3 Optimization of synthetic reaction 8
• 2. Structure-activity relationship and result of enzymatic and cellular inhibitory activities synthesis of c-KIT inhibitor derivatives 12
• 3. Molecular docking studies of 7s with c-KIT 20
• 4. Kinase selectivity profile 22
• Conclusion 24
• Materials and Methods 26
• Reference 48
• Abstract in Korean 53