title: Development and biological evaluation of potent and selective c-KIT(D816V) inhibitors.
abstract: The c-KIT tyrosine kinase has emerged as a potential therapeutic target for an array of diseases. However, there exists a drug resistance that is caused by mutations in c-KIT; therefore, c-KIT remains as a clinical challenge due to limited effective treatment options for therapies. For example, the acquired activating point mutation D816V significantly impairs the efficacy of targeted cancer therapies. Understanding the mechanisms of drug resistance at the molecular level will aid in designing and developing particular inhibitors with the potential to overcome these resistance mutations. We undertake a structure-based de novo design of 7-azaindole as the molecular core using the modified scoring function. This approach led to an identification of new c-KIT inhibitors over 100-fold specific for the D816V mutant relative to the wild-type c-KIT with nanomolar inhibitory activity. More importantly, these compounds potently inhibit clinically relevant D816V mutations of c-KIT in biochemical and cellular studies.
authors.affiliation: Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST) , Yuseong-gu, E6-4, Daejeon 305-701, Korea.
authors.forename: Soyoung
authors.initials: S
authors.lastname: Lee
authors.forename: Hyunseung
authors.initials: H
authors.lastname: Lee
authors.forename: Jinhee
authors.initials: J
authors.lastname: Kim
authors.forename: Suhyun
authors.initials: S
authors.lastname: Lee
authors.forename: Soo Jung
authors.initials: SJ
authors.lastname: Kim
authors.forename: Byong-Seok
authors.initials: BS
authors.lastname: Choi
authors.forename: Soon-Sun
authors.initials: SS
authors.lastname: Hong
authors.forename: Sungwoo
authors.initials: S
authors.lastname: Hong
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001372:Aza Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001549:Benzamides / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D015195:Drug Design; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D000068877:Imatinib Mesylate; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D062105:Molecular Docking Simulation; D010879:Piperazines / Q000494:pharmacology; D017354:Point Mutation; D019009:Proto-Oncogene Proteins c-kit / Q000037:antagonists & inhibitors* / Q000235:genetics; D011743:Pyrimidines / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D001372:Aza Compounds; D001549:Benzamides; D007211:Indoles; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit