Inhibitors of ras oncoprotein, methods of making and methods of use thereof

An alkyl, disease-based technology, applied in the field of RAS oncoprotein inhibitors and its preparation and use, can solve problems such as unapproved treatments

Pending Publication Date: 2021-02-02
UNIV OF LOUISVILLE RES FOUND INC
View PDF7 Cites 1 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] RAS inhibitors are known...

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
  • Inhibitors of ras oncoprotein, methods of making and methods of use thereof
  • Inhibitors of ras oncoprotein, methods of making and methods of use thereof
  • Inhibitors of ras oncoprotein, methods of making and methods of use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0092] Embodiment 1: the synthesis of compound

[0093] The corresponding amine R can be prepared by first 1 -NH 2 and R 2 -NH 2 , then with the diacid X 1 (CH 2 COOH) 2 Sequential reactions to prepare compounds of formula I, diacid X 1 (CH 2 COOH) 2 May optionally be in the form of a cyclic anhydride. In the examples below, R 1 and R 2 Contains substituted phenyl groups. In the first example, the substituted phenyl groups are labeled "A" and "B", respectively.

[0094]

[0095] Synthesis of sulfonamide fragments;

[0096]

[0097] Scheme 1. Synthesis of F3 sulfonamide fragment.

[0098] The synthesis of F3 starts with the construction of sulfonamide 4 (B ring of F3). The sulfonamide was prepared by treating commercially available sulfonyl chloride 1 with two equivalents of amine 2. Reduction of the nitro group 3 under catalytic hydrogenation conditions completed the synthesis in excellent overall yields. Various sulfonamide derivatives are prepared by s...

Embodiment 2

[0138] Embodiment 2: the test of compound

[0139] Binding test

[0140] Direct binding of F3 / F3a derivatives to recombinant K-RAS protein. Thermal fluorescence analysis was used to determine whether there was a direct interaction between the recombinant K-RAS protein and compound F3, or between the recombinant K-RAS protein and compound JAB-6-5. Recombinant K-RAS12v protein was loaded with γGTPS and used for binding assays at a ratio of 200 μM compound / 5 μM protein. Control compound C4 targets a different protein and is not expected to bind RAS. The assay results of the three derivatives were performed in triplicate. With the exception of C4, significant curve shifts were observed for both F3 and JAB-6-5. From the curve it can be deduced that the predicted kD is about 25 μM at 55.5°C. The result is as Figure 16 shown.

[0141] Three-dimensional soft agar drug screening (in vitro test)

[0142] The vast majority of solid tumors arise from epithelial cells. Normal epi...

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

A compound for use in treating a disease associated with activating mutations in RAS, or for use in treating a disease treatable by a reduction in RAS activity, is selected from a compound of Formula(I), salts and esters thereof. The compounds are particularly useful in treating cancer.

Description

[0001] government rights [0002] This invention was made with United States Government support: Grant No. RR018733 by the National Institutes of Health (NIH). The US Government has certain rights in this invention. Background technique [0003] RAS is the most common oncogene in human cancers. Activating mutations in one of the three human RAS oncogene subtypes (KRAS, HRAS, or NRAS) account for about a quarter of all cancers [1] . KRAS also exists in two alternatively spliced ​​forms, called KRAS4A and KRAS4B. For example, KRAS mutants are found in 98% of pancreatic ductal adenocarcinomas, 52% of colon cancers, and 32% of lung adenocarcinomas [1] . These three cancer types alone represent more than 170,000 KRAS-mutant cancers diagnosed and more than 120,000 deaths in the U.S. each year [2] . There are currently no FDA-approved direct RAS protein inhibitors. There are already drugs that target RAS downstream signaling, but they have shown disappointing clinical activit...

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): A61K31/167A61K31/18A61K31/55A61P35/00C07D223/04
CPCA61K31/167A61K31/18A61P35/00A61K31/55C07D295/26C07D295/192C07D317/58C07D317/66C07C311/46C07C2601/14C07C233/66A61K31/4453A61K31/40A61P35/02A61P35/04A61K31/36C07D223/06A61K31/357C07K16/2818
Inventor 杰弗里·J·克拉克约翰·O·特伦特约瑟夫·A·伯尔森
Owner UNIV OF LOUISVILLE RES FOUND INC
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Try Eureka
PatSnap group products

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

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap