BioCentury
ARTICLE | Distillery Therapeutics

Therapeutics: Heat shock 70 kDa protein 5 (glucose-regulated protein, 78kDa) (HspA5; GRP78)

June 2, 2016 7:00 AM UTC

In vitro, cell culture and mouse studies identified a thiazole-based HspA5 inhibitor that could help treat drug-resistant melanoma and other cancers. Chemical synthesis and in vitro testing of thiazole analogs identified a compound that decreased HspA5 activity in a human melanoma cell line compared with vehicle. In human melanoma, breast, colon, cervical, prostate, brain and pancreatic cancer cell lines, the compound decreased proliferation. In three Zelboraf vemurafenib-resistant melanoma cell lines, a Gemzar gemcitabine-resistant pancreatic cancer cell line and a Gleevec imatinib-resistant leukemia cell line, the compound decreased proliferation compared with the corresponding drug. In a xenograft mouse model of melanoma, the compound decreased tumor growth compared with vehicle, without causing weight loss or other observable toxicities. In a patient-derived xenograft mouse model of Zelboraf-resistant melanoma, the compound decreased tumor growth compared with vehicle or Zelboraf. Next steps could include testing the compound in animal models of other cancers.

Daiichi Sankyo Co. Ltd., Roche and Chugai Pharmaceutical Co. Ltd. market Zelboraf, an oral small molecule inhibitor of BRAF, to treat melanoma and have the compound in Phase II testing to treat thyroid cancer. ...