Looking for breakthrough ideas for innovation challenges? Try Patsnap Eureka!

Quinoline inhibitors of RAD52 and methods of use

A technology of N-R2 and solvates, applied in the field of small molecule modulators, can solve problems such as lethality and interruption

Pending Publication Date: 2022-05-03
DREXEL UNIV
View PDF28 Cites 0 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Inactivation of PARP1 and RAD52 causes lethality in BRCA1 / 2-deficient and PALB2-deficient cells through different mechanisms
Inactivation of PARP1 leads to disruption of DNA SSB repair

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Quinoline inhibitors of RAD52 and methods of use
  • Quinoline inhibitors of RAD52 and methods of use
  • Quinoline inhibitors of RAD52 and methods of use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0980] Example 1. Synthesis of Compounds of the Disclosure

[0981] General Synthetic Scheme for the Preparation of Compounds of Formula I

[0982] Reagents useful in the preparation of the compounds described herein are either commercially available or prepared by standard procedures described in the literature. Compounds of formula I' or formula I can be produced by one of the following reaction schemes.

[0983] A first aspect of the disclosed method relates to a method of preparing a quinoline having Formula I' or Formula I.

[0984] Compounds of Formula I' or Formula I can be prepared according to the methods outlined in Schemes 1-17.

[0985]

[0986] Scheme 11. Preparation of compounds of Formula I' or Formula I from reactions at the 6-amine group

[0987] Thus, an appropriately substituted compound of formula (A) (a known compound or a compound prepared by a known method) and compound B (a known compound or a compound prepared by a known method), optionally in an o...

Embodiment 2

[1284] Example 2. Cell Assays

[1285] cell line:

[1286] 1. BRCA1-deficient / healthy cell line: UWB1.298 / UWB1.298(BRCA1+)

[1287] 2. BRCA2 deficient / healthy cell line: Capan-1 / Capan-1(BRCA2+)

[1288] Program:

[1289] Capan-1 and Capan-1 (BRCA2+) cells were maintained in IMDM (ATCC) medium containing 20% ​​FBS (GIBCO). UWB1.298 and UWB1.298(BRCA1+) cells were maintained in 48.5% RPMI1640 (ATCC), 48.5% MEGM (Clonetics / Lonza, MEGM kit, CC-3150) and 3% FBS (GIBCO), respectively. The log phase cells were harvested, and 100 μl of the cell suspension was plated in a 96-well plate at a final density of 4000 cells / well. After overnight growth, cells were treated with the indicated concentrations of compounds. Medium containing constant concentrations of compound was refreshed every 3 days until cells were finally lysed with 30 μl / well of Promega CellTiter-Glo reagent and read on a Promega GloMax 96 reader at day 10 (9 days of exposure).

Embodiment 3

[1290] Example 3. Clonogenic Survival Assay

[1291] MDA-MB-436 cells were cultured in RPMI+10% FBS. BRCA-proficient and BRCA-deficient cells were plated at 5,000 cells / well on day 0 in triplicate. Cells were counted on day 4 using trypan blue exclusion on a hemocytometer and immediately plated at a density of 500 cells / well in 6-well plates in RPMI+10% FBS in the clonogenicity assay. After two weeks, colonies were fixed / stained with 0.05% of 10 mg / ml ethidium bromide in 50% ethanol and visualized with an Alphaimager gel imager (Alpha Innotech).

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

PUM

No PUM Login to View More

Abstract

The present disclosure relates to Formula I and compounds of Formula I and pharmaceutically acceptable salts, pharmaceutical compositions, methods of use, and methods of preparation thereof. The compounds disclosed herein can be used to modulate RAD51 activity, and can be used to treat conditions in which RAD51 activity is implicated, such as cancer.

Description

[0001] Cross References to Related Applications [0002] This application claims priority under 35 U.S.C. §119(e) to U.S. Provisional Application No. 62 / 909,017, filed October 1, 2019, the contents of which are incorporated herein by reference in their entirety. Background technique [0003] The present disclosure relates to small molecule modulators of RAD52 designed for the treatment of cancer and other disorders associated with RAD52. [0004] DNA repair is essential to maintain the integrity of the genome in all organisms. Numerous DNA repair systems have evolved to eliminate a variety of DNA lesions caused by exogenous substances or genotoxic products of metabolism. In normal cells, the specificities of different DNA repair mechanisms overlap to ensure efficient genome conservation. However, cancer cells often lose some DNA repair pathways due to intrinsic genomic instability. In this case, the viability of cancer cells depends on remaining alternative DNA repair mecha...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

Application Information

Patent Timeline
no application Login to View More
IPC IPC(8): C12N15/10C12N15/11C12N15/70
CPCC07D215/38C07D401/12C07D401/14A61P35/00A61P15/00C07D403/12A61K31/4709A61K31/55A61K31/5377A61K31/541A61K31/496C07D401/04
Inventor A·V·马津P·Y·S·拉姆K·哈纳姆谢M·S·帕特尔Y·杜N·黄
Owner DREXEL UNIV
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Patsnap Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Patsnap Eureka Blog
Learn More
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic, Popular Technical Reports.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap|About US| Contact US: help@patsnap.com