Identification of pyrrolo[2,3-d]pyrimidines as potent HCK and FLT3-ITD dual inhibitors

• Published in: Bioorganic & medicinal chemistry letters Vol. 27; no. 22; pp. 4994 - 4998
• Main Authors: Koda, Yasuko, Kikuzato, Ko, Mikuni, Junko, Tanaka, Akiko, Yuki, Hitomi, Honma, Teruki, Tomabechi, Yuri, Kukimoto-Niino, Mutsuko, Shirouzu, Mikako, Shirai, Fumiyuki, Koyama, Hiroo
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 15.11.2017; Elsevier
• Subjects: Acute myeloid leukemia (AML); Apoptosis - drug effects; Binding Sites; Cell Line, Tumor; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Crystallography, X-Ray; fms-Like Tyrosine Kinase 3 - antagonists & inhibitors; fms-Like Tyrosine Kinase 3 - metabolism; FMS-like tyrosine kinase 3 with internal tandem duplication mutations (FLT3-ITD); Hematopoietic cell kinase (HCK); Humans; Leukemia, Myeloid, Acute - metabolism; Leukemia, Myeloid, Acute - pathology; Life Sciences & Biomedicine; Molecular Docking Simulation; Pharmacology & Pharmacy; Physical Sciences; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - metabolism; Protein Kinase Inhibitors - toxicity; Protein Structure, Tertiary; Proto-Oncogene Proteins c-hck - antagonists & inhibitors; Proto-Oncogene Proteins c-hck - metabolism; Pyrimidines - chemistry; Pyrimidines - metabolism; Pyrimidines - toxicity; Pyrroles - chemistry; Pyrroles - metabolism; Pyrroles - toxicity; Pyrrolo[2,3-d]pyrimidine; Science & Technology; Structure-Activity Relationship; Thermodynamics; FMS-like tyrosine kinase 3 with internal tandem duplication mutations (FLT3-ITD); Pyrrolo[2,3-d]pyrimidine; Acute myeloid leukemia (AML); Hematopoietic cell kinase (HCK); CELLS; STAT5; ACUTE MYELOID-LEUKEMIA
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2017.10.012

Identification of HCK and FLT3-ITD dual inhibitors. [Display omitted] A series of novel pyrrolo[2,3-d]pyrimidines were synthesized by introducing 15 different amino acids to 7-cyclohexyl-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidine-4-amine. Compounds with potent activities against HCK and FLT3-ITD were evaluated in viability studies with acute myeloid leukemia cell line MV4-11. Our structure activity relationship analyses lead to the identification of compound 31, which exhibited potent HCK and FLT3-ITD inhibition and activity against the MV4-11 cell line.