Synthesis and evaluation of novel 2,4-diaminopyrimidines bearing bicyclic aminobenzazepines for anaplastic lymphoma kinase (ALK) inhibitor

  • Bioorg Med Chem Lett. 2015 Sep 15;25(18):3992-8. doi: 10.1016/j.bmcl.2015.07.004.
Ga Ae Kang  1 ,  Minji Lee  2 ,  Dawn Song  3 ,  Heung Kyoung Lee  1 ,  Sunjoo Ahn  4 ,  Chi Hoon Park  4 ,  Chong Ock Lee  1 ,  Chang Soo Yun  4 ,  Heejung Jung  4 ,  Pilho Kim  4 ,  Jae Du Ha  1 ,  Sung Yun Cho  4 ,  Hyoung Rae Kim  5 ,  Jong Yeon Hwang  6
Affiliations
  • 1. Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 305-600, Republic of Korea.
  • 2. Department of Chemistry, Korea University, Seoul 136-701, Republic of Korea.
  • 3. College of Pharmacy, Chungbuk National University, Cheongju, Chungbuk 362-763, Republic of Korea.
  • 4. Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 305-600, Republic of Korea; Department of Medicinal Chemistry and Pharmacology, University of Science & Technology, Daejeon 305-550, Republic of Korea.
  • 5. Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 305-600, Republic of Korea. Electronic address: [email protected].
  • 6. Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 305-600, Republic of Korea; Department of Medicinal Chemistry and Pharmacology, University of Science & Technology, Daejeon 305-550, Republic of Korea. Electronic address: [email protected].
PMID: 26235945 DOI: 10.1016/j.bmcl.2015.07.004
Abstract

A series of novel 2,4-diaminopyrimidine compounds bearing bicyclic aminobenzazepine were synthesized and evaluated for their anti-ALK activities. The activities of these compounds were confirmed in both enzyme- and cell-based ALK assays. Amongst compounds synthesized, KRCA-0445 showed very promising results in pharmacokinetic study and in vivo efficacy study with H3122 xenograft mouse model.

Keywords
2,4-Diaminopyrimidine; ALK; Cancer.