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Angew Chem Int Ed Engl 2021 Feb 23. Epub 2021 Feb 23.

Oklahoma State University Stillwater, chemistry, UNITED STATES.

The 90 kDa heat shock protein (Hsp90) is a molecular chaperone that processes nascent polypeptides into their biologically active conformations. Many of these proteins contribute to the progression of cancer, and consequently, inhibition of the Hsp90 protein folding machinery represents an innovative approach toward cancer chemotherapy. However, clinical trials with Hsp90 N-terminal inhibitors have encountered deleterious side effects and toxicities, which appear to result from the pan -inhibition of all four Hsp90 isoforms. Read More

J Med Chem 2021 Feb 23. Epub 2021 Feb 23.

The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.

The cytosolic Hsp90-selective inhibitor TAS-116 has an acceptable safety profile and promising antitumor activity in clinical trials. We examined the binding characteristics of TAS-116 and its analogs to determine the impact of the ligand binding mode on selectivity for cytosolic Hsp90. Analyses of the co-crystal structure of Hsp90 and inhibitor TAS-116 suggest that TAS-116 interacts with the ATP-binding pocket, the ATP lid region, and the hydrophobic pocket. Read More

Cancer Control 2021 Jan-Dec;28:1073274821989314

Department of Hepatobiliary Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, People's Republic of China.

Objective: Intrahepatic cholangiocarcinoma (iCCA), the second most common type of primary liver tumor, has an increasing incidence in the past few decades. iCCA is highly malignant, with a 5-year survival rate of approximately 5-10%. Surgical resection is usually the prescribed treatment for patients with early stage iCCA; however, patients are usually in an advanced stage iCCA upon diagnosis. Read More

Bioorg Med Chem Lett 2021 Feb 17:127857. Epub 2021 Feb 17.

School of Chemical Sciences, The University of Auckland, Private Bag 92019, Victoria Street West, Auckland 1142, New Zealand; Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Private Bag 92019, Victoria Street West, Auckland 1142, New Zealand. Electronic address:

Heat shock protein 90 (Hsp90) is an essential molecular chaperone that performs vital stress-related and housekeeping functions in cells and is a current therapeutic target for diseases such as cancers. Particularly, the development of Hsp90 C-terminal domain (CTD) inhibitors is highly desirable as inhibitors that target the N-terminal nucleotide-binding domain may cause unwanted biological effects. Herein, we report on the discovery of two drug-like novel Hsp90 CTD inhibitors by using virtual screening and intrinsic protein fluorescence quenching binding assays, paving the way for future development of new therapies that employ molecular chaperone inhibitors. Read More

Cell Chem Biol 2021 Feb;28(2):118-120

Department of Neurosurgery, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA. Electronic address:

HSP90 inhibitors are in numerous cancer clinical trials, but treatments often induce toxicity at effective dosages. In this issue of Cell Chemical Biology, Zavareh et al. (2020) serendipitously found that HSP90 inhibitors, at manageable doses, can reduce target cell expression of immune checkpoint molecules, potentially enabling improved anti-cancer immunotherapy. Read More