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Electrophiles and electrophile pro-drugs as rad51 inhibitors

A technology of DNA damage agent and anti-tumor agent, which can be used in the field of electrophilic reagents and electrophilic prodrugs as RAD51 inhibitors, and can solve problems such as harmfulness

Pending Publication Date: 2021-06-18
UNIVERSITY OF PITTSBURGH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

While RAD51 is essential for high-fidelity repair of DSBs to maintain genomic homeostasis, overexpression of RAD51 in cancer can also have deleterious consequences

Method used

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  • Electrophiles and electrophile pro-drugs as rad51 inhibitors
  • Electrophiles and electrophile pro-drugs as rad51 inhibitors
  • Electrophiles and electrophile pro-drugs as rad51 inhibitors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment

[0277] Experimental procedure - nitroalkene fatty acids impair RAD51 function and enhance the effects of DNA damaging agents on the growth of triple-negative breast cells

[0278] Cell Culture and Reagents

[0279] HEK 293T, MDA-MB-231, MDA-MB-468, Hs578T, and BT-549 cells (American TypeCulture Collection) were incubated at 37°C with 5% CO 2 Cultured in Dulbecco's modified Eagle medium containing 5% FBS (HyClone), 100 units / ml penicillin, 100 mg / ml streptomycin (Gibco), non-essential amino acids (Gibco) and 2 mM 1-glutamine (Gibco). Doxorubicin (Selleckchem), cisplatin (Sigma) or olaparib (Selleckchem) were dissolved in DMSO or DMF (cisplatin). Nitrooleic acid (10-octadec-9-enoic acid) (NO 2 -OA) and biotinylated NO 2 -OA. pure NO 2 -OA was diluted in DMSO and added to cells after solvation in assay medium. The relative number of cells was compared by measuring the luminescence signal produced by ATP by the Cell Titer Glo (Promega) method. Cells were seeded in 96-well p...

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Abstract

A method comprising co-administering to a subject having cancer, suspected of having cancer, or at risk of developing cancer: a therapeutically effective amount of at least one compound (a) selected from (a)(i) a nitroalkene fatty acid, (a)(ii) an unsaturated fatty acid having an electron withdrawing group, a leaving group, and a carbon-carbon double bond disposed between the electron withdrawing group and the leaving group, (a)(iii) a thiolated nitro fatty acid, or (a)(iv) a dicarboxylic acid compound containing an electron withdrawing group; and a therapeutically effective amount of at least one anti-neoplastic agent (b), wherein the cancer is a cancer with hereditary etiology of defects in DNA repair genes, a cancer with a high rate of spontaneous genomic instability, a cancer that responds well to DNA damaging agent(s), or a cancer that responds well to a combination of DNA damaging agent(s) with immunotherapy.

Description

[0001] Cross application in related field [0002] This application claims the benefit of U.S. Provisional Patent Application No. 62 / 767,424, filed November 14, 2018, which is incorporated herein by reference. [0003] Thanks for the support from the government [0004] This invention was made with government support Nos. HL058115, DK072506, HL103455, and HL064937 awarded by the National Institutes of Health. The government has certain rights in this invention. Background technique [0005] Triple-negative breast cancer (TNBC) accounts for approximately 20% of all breast cancers and is the most aggressive subtype of breast cancer. Due to the lack of estrogen and progesterone receptors and the receptor tyrosine kinase ERB2 (HER2) that defines most breast cancers, there are no targeted therapies for TNBC patients. Higher metastatic rates and lower 5-year survival rates compared with other breast cancer phenotypes suggest an unmet need for new treatment strategies. [0006...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/04A61K31/10A61K31/105A61K31/20A61K31/22A61K31/194C07C205/50C07C69/593C07C323/54A61P35/00
CPCA61K31/10A61P35/00C07C205/50A61K31/202A61K31/704A61K31/55A61K31/454A61K31/4184A61K31/5025A61K31/4745A61K45/06A61N2005/1098A61K2300/00A61K33/243A61K31/201A61K31/231A61K31/502
Inventor B·A·弗里曼C·纽曼恩F·J·朔普费尔
Owner UNIVERSITY OF PITTSBURGH
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