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 36 nM 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.
| Original language | English |
|---|---|
| Pages (from-to) | 237-241 |
| Number of pages | 5 |
| Journal | Bioorganic and Medicinal Chemistry Letters |
| Volume | 27 |
| Issue number | 2 |
| DOIs | |
| Publication status | Published - 2017 Jan 15 |
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Keywords
- Antiproliferative
- Cancer
- Hsp90
- Pyrrolo[2,3-d]pyrimidines
- Structure-based design
ASJC Scopus subject areas
- Biochemistry
- Molecular Medicine
- Molecular Biology
- Pharmaceutical Science
- Drug Discovery
- Clinical Biochemistry
- Organic Chemistry
Cite this
Synthesis and in vitro antiproliferative activity of C5-benzyl substituted 2-amino-pyrrolo[2,3-d]pyrimidines as potent Hsp90 inhibitors. / Lee, Ju Hyeon; Shin, Sang Chul; Seo, Seon Hee; Seo, Young Ho; Jeong, Nakcheol; Kim, Chan Wha; Kim, Eunice Eun Kyeong; Keum, Gyochang.
In: Bioorganic and Medicinal Chemistry Letters, Vol. 27, No. 2, 15.01.2017, p. 237-241.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Synthesis and in vitro antiproliferative activity of C5-benzyl substituted 2-amino-pyrrolo[2,3-d]pyrimidines as potent Hsp90 inhibitors
AU - Lee, Ju Hyeon
AU - Shin, Sang Chul
AU - Seo, Seon Hee
AU - Seo, Young Ho
AU - Jeong, Nakcheol
AU - Kim, Chan Wha
AU - Kim, Eunice Eun Kyeong
AU - Keum, Gyochang
PY - 2017/1/15
Y1 - 2017/1/15
N2 - 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 36 nM 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.
AB - 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 36 nM 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.
KW - Antiproliferative
KW - Cancer
KW - Hsp90
KW - Pyrrolo[2,3-d]pyrimidines
KW - Structure-based design
UR - http://www.scopus.com/inward/record.url?scp=85006850831&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85006850831&partnerID=8YFLogxK
U2 - 10.1016/j.bmcl.2016.11.062
DO - 10.1016/j.bmcl.2016.11.062
M3 - Article
VL - 27
SP - 237
EP - 241
JO - Bioorganic and Medicinal Chemistry Letters
JF - Bioorganic and Medicinal Chemistry Letters
SN - 0960-894X
IS - 2
ER -