Design, synthesis and molecular mechanisms of novel dual inhibitors of heat shock protein 90/phosphoinositide 3-kinase alpha (Hsp90/PI3Kα) against cutaneous melanoma.

Publisher: Taylor & Francis Country of Publication: England NLM ID: 101150203 Publication Model: Print Cited Medium: Internet ISSN: 1475-6374 (Electronic) Linking ISSN: 14756366 NLM ISO Abbreviation: J Enzyme Inhib Med Chem Subsets: MEDLINE

Original Publication: Basingstoke, UK : Taylor & Francis, c2002-

Drug Design*; Antineoplastic Agents/*chemistry ; Antineoplastic Agents/*pharmacology ; Enzyme Inhibitors/*chemistry ; Enzyme Inhibitors/*pharmacology ; HSP90 Heat-Shock Proteins/*antagonists & inhibitors ; Melanoma/*drug therapy ; Nuclear Proteins/*antagonists & inhibitors ; Skin Neoplasms/*drug therapy ; Transcription Factors/*antagonists & inhibitors; Animals ; Antineoplastic Agents/chemical synthesis ; Apoptosis/drug effects ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Chromatography, Gas ; Enzyme Inhibitors/chemical synthesis ; Female ; Humans ; Inhibitory Concentration 50 ; Melanoma/enzymology ; Melanoma/metabolism ; Melanoma/pathology ; Mice ; Mice, Inbred C57BL ; Neoplasm Invasiveness/prevention & control ; Neoplasm Metastasis/prevention & control ; Proton Magnetic Resonance Spectroscopy ; Skin Neoplasms/enzymology ; Skin Neoplasms/metabolism ; Skin Neoplasms/pathology ; Structure-Activity Relationship ; Xenograft Model Antitumor Assays

Overexpression of heat shock protein 90 (Hsp90) is common in various types of cancer. In cutaneous melanoma, a cancer with one of the high levels of Hsp90 overexpression, such expression was correlated with a panel of protein kinases, thus offering an opportunity to identify Hsp90-based multi-kinase inhibitors for novel cancer therapies. Towards this goal, we utilized a 2,4-dihydroxy-5-isopropylbenzate-based Hsp90 inhibitor scaffold and thieno[2,3-d]pyrimidine-based kinase inhibitor scaffold to develop a Hsp90-inhibiting compound library. Our inhibitory compound named 8m inhibited Hsp90 and PI3Kα with an IC 50 value of 38.6 nM and 48.4 nM, respectively; it displayed improved cellular activity which could effectively induce cell cycle arrest and apoptosis in melanoma cells and lead to the inhibition of cell proliferation, colony formation, migration and invasion. Our results demonstrated 8m to be a promising lead compound for further therapeutic potential assessment of Hsp90/PI3Kα dual inhibitors in melanoma targeted therapy.

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Keywords: Apoptosis; PI3Kα; hsp90; kinase inhibitor; melanoma

0 (Antineoplastic Agents)
0 (Enzyme Inhibitors)
0 (HSP90 Heat-Shock Proteins)
0 (Nuclear Proteins)
0 (PI3KCA protein, human)
0 (Transcription Factors)

Date Created: 20190409 Date Completed: 20190429 Latest Revision: 20220219

20221213

PMC8853710

10.1080/14756366.2019.1596903

30957641