HSP90 inhibitors under development for pancreatic cancer therapy

Celastrol is a triterpenoid compound (figure 1) which can be produced from the leaves of a plant used in traditional Chinese medicine called Tripterygium wilfordii  or 雷公藤 [1]. Celastrol prevents interaction between HSP90 and its cochaperone CDC37. It has no effect on ATP binding to HSP90 which most other inhibitors target [2].

celastrol
Figure 1: Celastrol. Credit: Ed (Edgar181). No changes were made. Creative Commons Public Domain Mark 1.0.

HSP90s are a family of chaperone proteins that function to stabilise, regulate and activate a range of so called client proteins [3]. The particular subset of client proteins they interact with is determined by the cochaperone. CDC37 facilitates the interaction of HSP90 with a number of kinases with important functions in cancer such as SRC, RAF1 and AKT [4].

Treatment of the cancer cell line Panc-1 with Celastrol induced apoptosis, reduced the tumour volume of Panc-1 mouse xenografts and increased the survival time of mice bearing those xenografts [2]. Clinical trials using other single agent HSP90 inhibitors for pancreatic cancer have not been successful to date [5,6]. However combination strategies that target chemotherapeutic agents via conjugation to HSP90 inhibitors and HSP90 inhibitor incorporation into nanoparticles are under development which may be more effective [7,8].

Refs

  1. William T. Chalmers James P. Kutney Phillip J. Salisbury Kenneth L. Stuart Phillip M. Townsley Brian R. Worth (1982). Method for producing tripdiolide, triptolide and celastrol, US patent US4328309A. 1982-05-04.
  2. Zhang T, Hamza A, Cao X, Wang B, Yu S, Zhan CG, Sun D. A novel Hsp90 inhibitor to disrupt Hsp90/Cdc37 complex against pancreatic cancer cells. Mol Cancer Ther. 2008 Jan;7(1):162-70. doi: 10.1158/1535-7163.MCT-07-0484. PubMed PMID: 18202019.
  3. Pearl LH. Review: The HSP90 molecular chaperone-an enigmatic ATPase. Biopolymers. 2016 Aug;105(8):594-607. doi: 10.1002/bip.22835. Review. PubMed PMID: 26991466.
  4. Pearl LH. Hsp90 and Cdc37 — a chaperone cancer conspiracy. Curr Opin Genet Dev. 2005 Feb;15(1):55-61. Review. PubMed PMID: 15661534.
  5. PhII Study STA-9090 as Second or Third-Line Therapy for Metastatic Pancreas Cancer. ClinicalTrials.gov Identifier NCT01227018
  6. Study of AUY922 in Metastatic Pancreatic Cancer Who Are Resistant to First Line Chemotherapy. ClinicalTrials.gov Identifier: NCT01484860
  7. Bobrov E, Skobeleva N, Restifo D, Beglyarova N, Cai KQ, Handorf E, Campbell K, Proia DA, Khazak V, Golemis EA, Astsaturov I. Targeted delivery of chemotherapy using HSP90 inhibitor drug conjugates is highly active against pancreatic cancer models. Oncotarget. 2016 Oct 13. doi: 10.18632/oncotarget.12642. PubMed PMID: 27779106.
  8. Rochani AK, Balasubramanian S, Ravindran Girija A, Raveendran S, Borah A, Nagaoka Y, Nakajima Y, Maekawa T, Kumar DS. Dual mode of cancer cell destruction for pancreatic cancer therapy using Hsp90 inhibitor loaded polymeric nano magnetic formulation. Int J Pharm. 2016 Sep 10;511(1):648-58. Doi: 10.1016/j.ijpharm.2016.07.048. PubMed PMID: 27469073.
Advertisements

One thought on “HSP90 inhibitors under development for pancreatic cancer therapy”

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out / Change )

Twitter picture

You are commenting using your Twitter account. Log Out / Change )

Facebook photo

You are commenting using your Facebook account. Log Out / Change )

Google+ photo

You are commenting using your Google+ account. Log Out / Change )

Connecting to %s