CN-120204224-B - KLHL24 ubiquitin ligase inhibitor and application thereof

Abstract

The invention discloses a high-throughput screening method and a high-throughput screening system for KLHL24 ubiquitin ligase inhibitors, which have high stability and good repeatability and are beneficial to the development of efficient screening of KLHL24 ubiquitin ligase inhibitors and related medicaments thereof. Based on the method, the invention screens out a plurality of KLHL24 ubiquitin ligase inhibitors which can be effectively used for treating diseases related to KLHL24, in particular diseases caused by KLHL24 mutation, such as hereditary epidermolysis bullosa, dilated cardiomyopathy, alopecia, atrophic scar and the like, and has a very good application prospect. In view of the function of KLHL24 in skin and hair regeneration, the inhibitor has a good application prospect in maintaining normal hair.

Inventors

• Request for anonymity
• Request for anonymity

Assignees

• 首都医学科学创新中心

Dates

Publication Date

20260505

Application Date

20240807

Claims (10)

1. 1. Use of a compound or a pharmaceutically acceptable salt or deuterated compound thereof for the manufacture of a medicament for the prophylaxis and/or treatment of a disease associated with KLHL24, said compound having the structure: wherein R B is-NO 2 ; R D is selected from H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl; The KLHL24 related disease is alopecia.
2. 2. Use of a compound or a pharmaceutically acceptable salt or deuterated compound thereof for the manufacture of a medicament for maintaining hair, said compound having the structure: wherein R B is-NO 2 ; R D is selected from H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl; the maintenance of hair includes promoting hair growth, promoting hair regeneration and self-repair, prolonging hair growth cycle, and preventing hair loss.
3. 3. The use according to claim 1 or 2, wherein R D is C 1 -C 6 alkyl.
4. 4. Use according to claim 3, wherein R D is methyl or ethyl.
5. 5. The use according to claim 1 or 2, wherein the compound has the structure: 。
6. 6. use according to claim 1 or 2, characterized in that the compound or a pharmaceutically acceptable salt or deuterated compound thereof is used alone or in combination with other kinds of active ingredients.
7. 7. The use according to claim 6, wherein the medicament further comprises one or more pharmaceutically acceptable excipients.
8. 8. The method according to claim 7, wherein the pharmaceutically acceptable adjuvant is selected from the group consisting of binders, lubricants, disintegrants, suspending agents, solubilizers, thickeners, stabilizers, preservatives, fillers, antioxidants, buffers.
9. 9. The use according to claim 1 or 2, wherein the pharmaceutical dosage form is selected from the group consisting of gastrointestinal dosage form, injection dosage form, respiratory tract dosage form, dermal dosage form, luminal dosage form.
10. 10. The use according to claim 9, wherein the pharmaceutical dosage form is selected from the group consisting of oral dosage form, dermal dosage form, injectable dosage form.

Description

KLHL24 ubiquitin ligase inhibitor and application thereof Technical Field The invention relates to the technical field of medicines, in particular to a KLHL24 ubiquitin ligase inhibitor and application thereof. Background KLHL24 belongs to the Kelch-like gene family (Kelch-LIKE FAMILY proteins, KLHLs) which encodes proteins with a highly conserved BTB domain and BACK domain which interact with CUL3 and RBX1 to form the CUL3-RBX1-Kelch ubiquitin ligase complex. The Kelch-like protein also has a Kelch domain that serves to recruit substrates, determining the specificity of its E3 ligase. KLHL24 is widely expressed in various tissues of the human body, including the skin. The study conducted by the first inventor of the present invention found for the first time that the start codon mutation of Klhl gene produced truncated KLHL 24-delta N28 protein, which was more stable due to the reduced degree of ubiquitination, thus leading to the ubiquitination and degradation of a large amount of keratin KRT14 by KLHL24 in the skin, leading to the fragile and easy shedding of epidermal basal layer cells, and finally leading to the occurrence of hereditary bullous epidermolysis （Lin, Zhimiao, et al. Stabilizing mutations of KLHL24 ubiquitin ligase cause loss of keratin 14 and human skin fragility.Nature genetics48.12 (2016): 1508-1516.）., and the subsequent study reported that the ubiquitination substrates of KLHL24, besides KRT14, also include KRT15, vimentin and Desmin. Additional studies have found that the phenotype of syndromes resulting from KLHL24 mutations is occurring. EBS-KLHL24 patients have extensive bare skin areas and skin fragility at birth, develop atrophic scars over time, and patients with life threatening cardiomyopathy (Yenamandra, V.K., et al. Cardiomyopathy in patients with epidermolysis bullosa simplex with mutations in KLHL24.British Journal of Dermatology(2018) 179(5):1181-1183).EBS-KLHL24 may experience hair loss, especially at skin atrophy sites, sometimes even affecting the visibility of terminal hair （Cui, Jun, et al. KLHL24-Mediated Hair Follicle Stem Cells Structural Disruption Causes Alopecia.Journal of Investigational Dermatology (2022) 142(8):2079-2087）., and development of drugs against KLHL24 targets is of great significance. However, there is currently no specific drug for the treatment of diseases caused by KLHL24 mutations. Therefore, the establishment of a high-throughput screening system and the successful screening of drugs capable of specifically binding and inhibiting the activity of KLHL24 are of great significance for the treatment of diseases caused by KLHL24 mutation. In view of the function of KLHL24 in skin and hair regrowth, screening for this inhibitor is also of great importance in maintaining normal hair. Disclosure of Invention In order to overcome the defects of the prior art, the invention provides a KLHL24 ubiquitin ligase inhibitor and application thereof, and establishes a high throughput screening method and a high throughput screening system of the KLHL24 ubiquitin ligase inhibitor. In a first aspect of the invention there is provided the use of a compound, or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate or deuterated compound thereof, as an inhibitor of KLHL24 ubiquitin ligase, said compound having the structure: (I) Wherein, the Represents a single bond or a double bond; X is selected from O, S, NH; Ring A is heterocycle; R A is one or more independent substituents on the A ring selected from H, halogen, hydroxy, amino, cyano, nitro, azido, C 1-C10 alkyl, - (C 0-C6 alkylene) - (C 3-C10 cycloalkyl), - (C 0-C6 alkylene) - (C 6-C10 aryl), - (C 0-C6 alkylene) - (4-10 membered heterocyclyl), and, ; L is a divalent group attached to the A ring selected from the group consisting of a single bond, H, C 1-C6 alkylene, - (C 0-C6 alkylene) -O-, - (C 0-C6 alkylene) -S-, - (C 0-C6 alkylene) -C (O) -, -C (O) - (C 0-C6 alkylene) -, - (C 0-C6 alkylene) -COO-, - (C 0-C6 alkylene) -C (S) -, - (C 0-C6 alkylene) -N (C 0-C10 alkylene) -, - (C 0-C6 alkylene) -CON (C 0-C10 alkylene) -, - (C 0-C6 alkylene) -N (C 0-C10 alkylene) CO- - (C 0-C6 alkylene) -SO 2-、-(C0-C6 alkylene) -SO-, - (C 0-C6 alkylene) - (C 3-C10 cycloalkyl), - (C 0-C6 alkylene) - (C 6-C10 aryl), - (C 0-C6 alkylene) - (4-10 membered heterocyclylene) wherein the C 0-C6 alkylene, H in C 3-C10 cycloalkyl, C 6-C10 aryl, 4-10 membered heterocyclylene may be optionally substituted with one or more groups selected from halogen, cyano, nitro, azido, C 1-C10 alkyl, C 1-C10 haloalkyl, -O (C 0-10 alkyl), -S (C 0-10 alkyl), -SO 2(C0-10 alkyl), -SO 2N(C0-10 alkyl) (C 0-10 alkyl), -COO (C 0-10 alkyl), -OCO (C 0-10 alkyl), -CON (C 0-10 alkyl) (C 0-10 alkyl), -CO (C 0-10 alkyl), -N (C 0-10 alkyl) (C 0-10 alkyl), -N (C 0-10 alkyl) CO (C 0-10 alkyl), -N (C 0-10 alkyl) COO (C 0-10 alkyl), -N (C 0-10 alkyl) CON (C 0-10 alkyl), -N (C 0-10 alkyl) SO 2(C0-10 alkyl); r C is one or more indep