Application of BRAF inhibitor to preparation of novel drugs for treating programmed necrotic diseases and screening method of BRAF inhibitor

Abstract

The invention discloses application of a BRAF inhibitor to preparation of novel drugs for treating programmed necrotic diseases and a screening method of the BRAF inhibitor. The method is characterized by taking necrotic pathway sensitive cell line L929-FADD gene knockout cell strains as model cells of cell proliferation and necrosis, screening out small-molecule compounds influencing and inhibiting cell death from an FDA drug library, detecting different drug concentration of the small-molecule compounds obtained by screening, determining toxicity-effect concentration, and performing comprehensive evaluation from toxicity and recovery efficiency to obtain the BRAF inhibitor; and through inhibition of the BRAF inhibitor on cell necrosis, the BRAF inhibitor can be used for preparing novel drugs for treating the programmed necrotic diseases. The BRAF inhibitor has excellent necrosis inhibition effects on necrotic sensitive cell line L929-FADD knockout strains, human cell line HT29 and animal models; the water solubility of the BRAF inhibitor is better than that of Nec-1; the BRAF inhibitor is an FDA-approved clinical drug; the targeting property and the safety of the BRAF inhibitor are guaranteed; and the BRAF inhibitor is easy for clinical promotion.

Description

technical field [0001] The present invention relates to the field of cytology and pharmacology, in particular to the use of BRAF inhibitors in the preparation of novel drugs for treating programmed necrosis diseases, and also to the screening method for preparing new drugs for treating programmed necrosis diseases. Background technique [0002] The dynamic balance between orderly proliferation, differentiation and death of cells is the primary condition for maintaining the homeostasis of the internal environment. Programmed necrosis is an important way of cell death. It is a protein kinase through RIP3 and RIP1, and its interaction and phosphorylation affect necroptosis. Cell necrosis is a death process in which cells are subjected to strong physical, chemical or biological factors that cause disordered changes in cells. It is manifested as cell swelling, cell membrane rupture, cell content overflow, nuclear changes are slow, DNA degradation is insufficient, and local severe...

AI Technical Summary

Problems solved by technology

[0005] Traditional screening of drugs based on natural products or small molecule compound libraries has two main defects. One is the long R&D time and high investment risk in the development and innovation of new drugs and therapeutic biological products; the other is the solubility and safety of the screened drugs. Urgent need for animal and clinical validation

At the same time, the drug screening and application of targeted necrosis inhibitors currently mainly have the following shortcomings, including: (1) The necrostatin family represented by Nec-1 is a small molecular compound, although it is easy to pass through the blood Brain barrier is a good tool for molecular mechanism research, but because its compound family is insoluble in water or electrolyte solutions, it is difficult to use it as a clinical drug for new drug development; (2) Nec-1 is not a marketed drug approved by the Food and Drug Administration. The safety, cytotoxicity and tissue toxicity in the body lack data support, which is not conducive to the evaluation and application of new clinical drugs in the later stage; (3) most of the existing new drug screening platforms are based on the screening of unknown natural products or compounds, and the input cost is high, and the screening cycle and The verification experiment takes a long time; (4) The drugs screened based on unknown compounds have unclear targeting to the human body and lack data on cytotoxicity, cell metabolism, drug toxicology, and pharmacokinetics; (5) currently available Some screening platforms are based on common cell lines or animals, and the model cells used in the screening platforms are not conducive to judging the sensitivity of drugs to necroptosis.

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