Interesting (to me) new paper out of Stanford [1].
Chalcones are intermediaries in flavonoid biosynthesis in plants. Those who are interested in the vast array of natural polyphenols with anticancer properties, will scarcely be aware of chalcones, since they do not accumulate to any great extent.
SU086 is a bioavailable chalcone - but don't worry, it is a drug & very likely comfortingly expensive, if it pans out.
Heat shock proteins [HSPs] are cell survival proteins that protect besieged cancer cells via chaperone & other services. They are upregulated in PCa. HSP70 has almost 400 PCa hits on PubMed. It is a recognized target.
SU086 binds to HSP70 and acts to downregulate it.
From the new paper:
"We demonstrate that SU086 inhibits the growth of prostate cancer cells in vitro, cell-line and patient-derived xenografts in vivo, and ex vivo prostate cancer patient specimens."
"Furthermore, SU086 in combination with standard of care second-generation anti-androgen therapies displays increased impairment of prostate cancer cell and tumor growth in vitro and in vivo." {There is synergy with Enzalutamide.}
"Cellular thermal shift assay reveals that SU086 binds to heat shock protein 90 (HSP90) and leads to a decrease in HSP90 levels. Proteomic profiling demonstrates that SU086 binds to and decreases HSP90. Metabolomic profiling reveals that SU086 leads to perturbation of glycolysis.
"Our study identifies SU086 as a treatment for advanced prostate cancer as a single agent or when combined with second-generation anti-androgens."
***
I am not known for reporting on drugs at such an early stage of development, but humor me on this one.
-Patrick
[1] pubmed.ncbi.nlm.nih.gov/352...
Cell Rep Med
. 2022 Feb 2;3(2):100502. doi: 10.1016/j.xcrm.2021.100502. eCollection 2022 Feb 15.
SU086, an inhibitor of HSP90, impairs glycolysis and represents a treatment strategy for advanced prostate cancer
Meghan A Rice 1 2 , Vineet Kumar 3 , Dhanir Tailor 3 4 5 , Fernando Jose Garcia-Marques 1 2 , En-Chi Hsu 1 2 , Shiqin Liu 1 2 , Abel Bermudez 1 2 , Vijayalakshmi Kanchustambham 6 , Vishnu Shankar 6 , Zintis Inde 7 , Busola Ruth Alabi 1 2 , Arvind Muruganantham 1 2 , Michelle Shen 1 2 , Mallesh Pandrala 3 4 5 , Rosalie Nolley 8 , Merve Aslan 1 2 , Ali Ghoochani 1 2 , Arushi Agarwal 1 2 , Mark Buckup 1 2 , Manoj Kumar 1 2 , Catherine C Going 1 2 , Donna M Peehl 8 9 , Scott J Dixon 7 , Richard N Zare 6 , James D Brooks 2 8 , Sharon J Pitteri 1 2 , Sanjay V Malhotra 3 4 5 , Tanya Stoyanova 1 2
Affiliations collapse
Affiliations
1 Department of Radiology, Stanford University, Stanford, CA 94305, USA.
2 Canary Center at Stanford for Cancer Early Detection, Stanford University, Stanford, CA 94305, USA.
3 Department of Radiation Oncology, Stanford University, Stanford, CA 94305, USA.
4 Department of Cell, Development and Cancer Biology, Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA.
5 Center for Experimental Therapeutics, Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA.
6 Department of Chemistry, Stanford University, Stanford, CA 94305, USA.
7 Department of Biology, Stanford University, Stanford, CA 94305, USA.
8 Department of Urology, Stanford University, Stanford, CA 94305, USA.
9 Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA 94143, USA.
PMID: 35243415 PMCID: PMC8861828 DOI: 10.1016/j.xcrm.2021.100502
Abstract
Among men, prostate cancer is the second leading cause of cancer-associated mortality, with advanced disease remaining a major clinical challenge. We describe a small molecule, SU086, as a therapeutic strategy for advanced prostate cancer. We demonstrate that SU086 inhibits the growth of prostate cancer cells in vitro, cell-line and patient-derived xenografts in vivo, and ex vivo prostate cancer patient specimens. Furthermore, SU086 in combination with standard of care second-generation anti-androgen therapies displays increased impairment of prostate cancer cell and tumor growth in vitro and in vivo. Cellular thermal shift assay reveals that SU086 binds to heat shock protein 90 (HSP90) and leads to a decrease in HSP90 levels. Proteomic profiling demonstrates that SU086 binds to and decreases HSP90. Metabolomic profiling reveals that SU086 leads to perturbation of glycolysis. Our study identifies SU086 as a treatment for advanced prostate cancer as a single agent or when combined with second-generation anti-androgens.
Keywords: HSP90; combination therapy; glycolysis; metabolism; prostate cancer; therapeutics; therapy.
© 2021 The Author(s).
Conflict of interest statement
T.S., S.V.M., M.A.R., V. Kumar, and D.T. are contributors to a provisional patent application, U.S. Application Serial No. 63/023,031, “Methoxychalcone Derivative and Uses Thereof.” T.S. currently has consulting relationships with Dren Bio.
