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

  • Bioorg Med Chem Lett. 2017 Nov 15;27(22):4994-4998. doi: 10.1016/j.bmcl.2017.10.012.
Yasuko Koda  1 ,  Ko Kikuzato  1 ,  Junko Mikuni  2 ,  Akiko Tanaka  2 ,  Hitomi Yuki  3 ,  Teruki Honma  3 ,  Yuri Tomabechi  2 ,  Mutsuko Kukimoto-Niino  2 ,  Mikako Shirouzu  2 ,  Fumiyuki Shirai  1 ,  Hiroo Koyama  4
Affiliations
  • 1. Drug Discovery Chemistry Platform Unit, RIKEN Center for Life Science Technologies, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
  • 2. Drug Discovery Structural Biology Platform Unit, RIKEN Center for Life Science Technologies, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan.
  • 3. Drug Discovery Computational Chemistry Platform Unit, RIKEN Center for Life Science Technologies, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan.
  • 4. Drug Discovery Chemistry Platform Unit, RIKEN Center for Life Science Technologies, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan. Electronic address: [email protected].
PMID: 29037944 DOI: 10.1016/j.bmcl.2017.10.012
Abstract

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.

Keywords
Acute myeloid leukemia (AML); FMS-like tyrosine kinase 3 with internal tandem duplication mutations (FLT3-ITD); Hematopoietic cell kinase (HCK); Pyrrolo[2,3-d]pyrimidine.