Histone Deacetylase Inhibitors as Treatment for Targeting Multiple

Feb 22, 2018 - Allosteric Modulators of Nicotinic Acetylcholine Receptors Useful for the Treatment of Cognitive Impairment. ACS Medicinal Chemistry Le...
0 downloads 0 Views 449KB Size
Patent Highlight Cite This: ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX

Histone Deacetylase Inhibitors as Treatment for Targeting Multiple Components in Cancer Therapy Robert B. Kargbo* Usona Institute, 277 Granada Drive, San Luis Obispo, California 93401-7337, United States L is absent or a linking moiety, wherein the linking moiety is optional alkyl, substituted heteroalkyl, cycloalkyl, alkenyl, alkynyl, substituted aryl, and so forth. Key Structures.

Important Compound Classes.

Title. Histone Deacetylase and Histone Methyltransferase Inhibitors and Methods of Making and Use of the Same Patent Application Number. WO 2018/005799 A1 Publication Date. January 04, 2018 Priority Application. US 62/356,124 Priority Date. June 29, 2016 Inventors. Wang, P. G.; Kondengaden, M. S.; Zhang, Q.; Zang, L. Assignee Company. Georgia State University Research Foundation, Inc. Disease Area. Cancers Biological Target. Histone deacetylase and histone methyltransferase Summary. Histone deacetylases (HDACs) are a class of enzymes that catalyze the removal of acetyl functional groups from lysine residues of both histones and nonhistone proteins. The histones are highly packed, allowing the DNA into structural units in which DNA winds tightly, and play a crucial role in gene regulation. In a normal cell, high affinity-binding between the histones and the DNA backbone prevent transcription. However, histone acetyl transferases (HATs) are enzymes that acetylate conserved lysine amino acids, which neutralizes charged histone and decreases the ability of the histones to bind tightly to DNA. This invention involves a small molecule that targets multiple components in aberrant activity of HDACs and HATs. Histone deacetylases inhibitors (HDACIs) can result in either upregulation or repression of genes, which can induce apoptosis in both solid and hematological malignancies. In addition, protein lysine methyltransferase G9a catalyzes methylation of lysine 9 of histone H3 (H3K9), which is overexpressed in many cancers. Knockdown of G9a in lung, prostate, and leukemia cancer cells resulted in the inhibition of cell growth. Compounds in this invention are aimed to provide new anticancer agents that inhibit both HDAC and methyltransferase G9a. Definitions. X is absent or is oxygen (O), nitrogen (N), or sulfur (S). R1 hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl. R2, R3, and R5 are independently hydrogen, alyl, alkoxyl, heteroalkyl, cycloalkyl, alkylaryl, heteroaryl, and so forth. R4 and R6 are independently hydrogen, substituted alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, substituted alkenyl, alkynyl, or substituted aryl. © XXXX American Chemical Society

Biological Assay: HDAC Activity Assay. HeLa cells were seeded into 96-well cell culture plates and incubated under standard conditions. The inhibitors were added, and after standard alterations, fluorescence was measured at excitation of k = 355 nm and emission of k = 460 nm, which uses A549 and K562 cell lines, respectively. IC50s were then calculated using GraphPad Prizm statistical package with sigmoidal variable slope dose response curve fit. G9a H3K9me2 Cellular Assay. Cells were seeded at 8000−10000 cells in 96-well plates and exposed to various concentrations for 2 days. After standard alterations, including exposure the primary H3K9me2 antibody, the prepared plates were read on an Odyssey CLx scanner at both 800 nm (H3K9me2 signal) and 700 nm channels. IC50s were then calculated using GraphPad Prizm statistical package with sigmoidal variable slope dose response curve fit. Biological Data. The Table below shows H3K9Me2 cell immunofluorescence in-cell Western (ICW) assay results (MDA-B-231 cell line), which are compared to the parent compound BIX-01294.

Received: February 13, 2018

A

DOI: 10.1021/acsmedchemlett.8b00068 ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX

ACS Medicinal Chemistry Letters

Patent Highlight

The Table below shows cell based homogenous HDAC assay results, which are compared to the IC50 of SAHA (N-hydroxyN'-phenyl-octanediamide).

Recent Review Articles. 1) Harrison, I. F.; Smith, A. D.; Dexter, D. T. Neurosci. Lett. 2018, 666, 48. 2) Richters, A.; Koehler, A. N. Curr. Med. Chem. 2017, 24, 4121. 3) Ho, C. F.-Y.; Bon, C. P.-E.; Ng, Y.-K.; Herr, D. R.; Wu, J.S.; Lin, T.-N.; Ong, W.-Y. Neurochem. Res. 2017, DOI: 10.1007/s11064-017-2448-9. 4) Chrun, E. S.; Modolo, F.; Daniel, F. I. Pathol. Res. Pract. 2017, 213, 1329. 5) Sunami, Y.; Araki, M.; Kan, S.; Ito, A.; Hironaka, Y.; Imai, M.; Morishita, S.; Ohsaka, A.; Komatsu, N. J. Biol. Chem. 2017, 292, 2815.



AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Robert B. Kargbo: 0000-0002-5539-6343 Notes

The author declares no competing financial interest.

B

DOI: 10.1021/acsmedchemlett.8b00068 ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX