펀시스템, 비교과 통합정보시스템

- 세미나 일정 및 장소 : 2019년 12월 5일 목요일 16:30~, 형남공학관 116호

- 세미나 주제 : 고형 종양 치료를 위한 발암성 단백질 KRASG12C의 공유결합성 억제제 AMG 510의 인체에서의 첫 발견

(Discovery of AMG 510, a First-in-human Covalent Inhibitor of KRASG12C 

for the Treatment of Solid Tumors).

- 세미나 대상 : 화학과 논문연구 수강생 및 학부 재학생

- 세미나 목적 : 연사를 초청하여 화학과 관련한 분야의 최신 연구 동향을 소개합니다. 본 세미나는 암, 퇴행성 질환 등을 표적으로 하는 국내·외 신약 개발 연구 중 하나의 사례에 관한 강연입니다. 학부생들은 세미나를 통한 지식습득으로 차후 졸업 논문 작성에 도움을 받을 수 있습니다. 나아가 제약산업 및 학술기관에서의 연구 절차를 간적접으로 경험함으로써, 전공 관련 진로 선택을 함에 있어 좋은 동기가 될 수 있을 것입니다.

<Discovery of AMG 510, a First-in-human Covalent Inhibitor of KRASG12C 

for the Treatment of Solid Tumors.>

연사 : 신 영 숙 박사(숭실대 화학과)

     The RAS gene family encodes the small GTPase proteins NRAS, HRAS, and KRAS. KRAS is one of the most frequently mutated oncogenes in human cancer, with KRASp.G12D, p.G12V, and p.G12C constituting the major mutational subtypes across lung, colon, and pancreatic cancers. Despite over three decades of research, indirect approaches targeting KRAS mutant cancers have largely failed to show clinical benefit, and direct approaches have been limited by the apparent ‘undruggable’ nature of KRAS. The cysteine at position 12 of KRASG12C has emerged as a unique vulnerability that can be directly targeted with covalent inhibitors, and a small number of tool molecules have been disclosed. Our approach to KRASG12C inhibitors involved iterative electrophile library design and screening campaigns. In one series, co-crystal structures of improved molecules revealed that a side-chain motion exposed a shallow groove that was occupied by ligand atoms. To further enhance potency and drug-like properties, scaffold hopping was employed, leading to a new series characterized by an N-aryl quinazolin-2(1H)-one core. Extensive optimization of this series was conducted, and a highly potent, selective, and well-tolerated covalent inhibitor of KRASG12C was identified and nominated for clinical development as AMG 510. In preclinical KRASG12C tumor models, AMG 510 rapidly binds irreversibly to KRASG12C and provides a long duration of mitogen activated protein kinase (MAPK) pathway suppression, and when dosed orally once daily as a single agent is capable of inducing tumor regression. AMG 510 can also be combined safely and effectively with chemotherapy, targeted therapy, and immunotherapy in preclinical models. AMG 510 is, to the best of our knowledge, the first direct KRASG12C therapeutic to reach human clinical testing, and is currently in a Phase I clinical trial evaluating safety, tolerability, PK, and efficacy in subjects with solid tumors with the KRASp.G12C mutation (NCT03600883).