2. Academic Validation
  3. Synthesis and in vitro antiproliferative activity of C5-benzyl substituted 2-amino-pyrrolo[2,3-d]pyrimidines as potent Hsp90 inhibitors

Synthesis and in vitro antiproliferative activity of C5-benzyl substituted 2-amino-pyrrolo[2,3-d]pyrimidines as potent Hsp90 inhibitors

  • Bioorg Med Chem Lett. 2017 Jan 15;27(2):237-241. doi: 10.1016/j.bmcl.2016.11.062.
Ju-Hyeon Lee 1,  Sang Chul Shin 2,  Seon Hee Seo 3,  Young Ho Seo 4,  Nakcheol Jeong 5,  Chan-Wha Kim 6,  Eunice EunKyeong Kim 7,  Gyochang Keum 8
Affiliations

Affiliations

  • 1 Center for Neuro-Medicine, Korea Institute of Science and Technology (KIST), Hwarangro 14-gil 5, Seongbuk-gu, Seoul 02792, Republic of Korea; Department of Chemistry, Korea University, Anam-ro 145, Seongbuk-gu, Seoul 02841, Republic of Korea.
  • 2 Biomedical Research Institute, KIST, Hwarangro 14-gil 5, Seongbuk-gu, Seoul 02792, Republic of Korea; School of Life Sciences and Biotechnology, Korea University, Seoul 02841, Republic of Korea.
  • 3 Center for Neuro-Medicine, Korea Institute of Science and Technology (KIST), Hwarangro 14-gil 5, Seongbuk-gu, Seoul 02792, Republic of Korea.
  • 4 College of Pharmacy, Keimyung University, Daegu 42601, Republic of Korea.
  • 5 Department of Chemistry, Korea University, Anam-ro 145, Seongbuk-gu, Seoul 02841, Republic of Korea.
  • 6 School of Life Sciences and Biotechnology, Korea University, Seoul 02841, Republic of Korea.
  • 7 Biomedical Research Institute, KIST, Hwarangro 14-gil 5, Seongbuk-gu, Seoul 02792, Republic of Korea. Electronic address: eunice@kist.re.kr.
  • 8 Center for Neuro-Medicine, Korea Institute of Science and Technology (KIST), Hwarangro 14-gil 5, Seongbuk-gu, Seoul 02792, Republic of Korea. Electronic address: gkeum@kist.re.kr.
PMID: 27914802 DOI: 10.1016/j.bmcl.2016.11.062
Abstract

A novel series of heat shock protein 90 (HSP90) inhibitors was identified by X-ray crystal analysis of complex structures at solvent-exposed exit pocket C. The 2-amino-pyrrolo[2,3-d]pyrimidine derivatives, 7-deazapurines substituted with a benzyl moiety at C5, showed potent HSP90 inhibition and broad-spectrum antiproliferative activity against NCI-60 Cancer cell lines. The most potent compound, 6a, inhibited HSP90 with an IC50 of 36nM and showed a submicromolar mean GI50 value against NCI-60 cell lines. The interaction of 6a at the ATP-binding pocket of HSP90 was confirmed by X-ray crystallography and Western blot analysis.

Keywords

Antiproliferative; Cancer; Hsp90; Pyrrolo[2,3-d]pyrimidines; Structure-based design.

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