2. Academic Validation
  3. Discovery of hybrid Hsp90 inhibitors and their anti-neoplastic effects against gefitinib-resistant non-small cell lung cancer (NSCLC)

Discovery of hybrid Hsp90 inhibitors and their anti-neoplastic effects against gefitinib-resistant non-small cell lung cancer (NSCLC)

  • Bioorg Med Chem Lett. 2014 Jan 1;24(1):224-7. doi: 10.1016/j.bmcl.2013.11.034.
Chul-Ho Jeong 1,  Hee Baek Park 2,  Won Jun Jang 3,  Su Hyun Jung 2,  Young Ho Seo 4
Affiliations

Affiliations

  • 1 College of Pharmacy, Keimyung University, Daegu 704-701, South Korea; Institute for New Drug Development, Keimyung University, Daegu 704-701, South Korea.
  • 2 Institute for New Drug Development, Keimyung University, Daegu 704-701, South Korea.
  • 3 College of Pharmacy, Keimyung University, Daegu 704-701, South Korea.
  • 4 College of Pharmacy, Keimyung University, Daegu 704-701, South Korea; Institute for New Drug Development, Keimyung University, Daegu 704-701, South Korea. Electronic address: seoyho@kmu.ac.kr.
PMID: 24345447 DOI: 10.1016/j.bmcl.2013.11.034
Abstract

Heat shock protein 90 (HSP90) represents an attractive Cancer therapeutic target due to its role in the stabilization and maturation of many oncogenic proteins. We have designed a series of hybrid HSP90 inhibitors by connecting the resorcinol ring of VER-49009 (2) and the trimethoxyphenyl ring of PU3 (3) using structure-based approach. Subsequent testing established that compound 1f inhibited gefitinib-resistant H1975 cell proliferation, brought about the degradation of HSP90 client proteins including EGFR, Met, Her2 and Akt and induced the expression of HSP70. The design, synthesis, and evaluation of 1f are described herein.

Keywords

Gefitinib resistance; Hsp90; Inhibitor; Lung cancer; Rational design.

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