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제116회 대한화학회 학술발표회, 총회 및 기기전시회 안내 Discovery of 2,4-diaminopyrimidines with tetrahydroisoquinolines at the 2-position of pyrimidine as ALK inhibitors

2015년 9월 3일 16시 34분 37초
KCS.O-10 이곳을 클릭하시면 발표코드에 대한 설명을 보실 수 있습니다.
목 10시 : 40분
Oral Presentation for Young International Chemists
저자 및
AcharyRaghavendra, 윤정인1, 채종학2, 하재두3, 황종연4, 윤창수5, 정희정6, 조성윤3, 김형래3,*, 김필호7,*
한국화학연구원 의약바이오본부, Korea
1충남대학교 약학대학, Korea
2한국화학연구원 신물질연구본부/신약플랫폼기술팀, Korea
3한국화학연구원 난치성질환치료제연구센터, Korea
4한국화학연구원 신약연구본부, Korea
5한국화학연구원 신약연구본부 의약화학연구센터, Korea
6한국화학연구원 의약화학연구센터, Korea
7한국화학연구원 난치성질환치료제연구그룹, Korea
For the past ten years, Anaplastic Lymphoma Kinase (ALK), a receptor tyrosine kinase, has captivated tremendous interest due to its oncogenic potential and crucial role in the pathogenesis of a wide range of human cancers. To date there have been about a dozen ALK inhibitors entered into the clinical trials. Crizotinib is the first US FDA approved drug targeting ALK for the treatment of non-small cell lung cancer (NSCLC) patients. However, in the clinics crizotinib resistance was discovered due to point-mutations developed in patients treated with crizotinib. To overcome this resistance issue, second-generation ALK inhibitors have been developed and several of them are now in clinical trials, including LDK378 and CH542802. As our ongoing search for novel ALK inhibitors, we explored intensive modification at the 2-position of pyrimidine side chain in LDK378 to improve selectivity, physical property, in vitro, and in vivo efficacies. Through this effort, tetrahydroisoquinolines (THIQ) were discovered as suitable substituents for the 2-position structural fragment. Herein, we will present synthesis of THIQ analogs, and in vitro and in vivo activities of selected THIQ compounds.