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CN-121974907-A - TRIM 15-targeted small molecule conjugate and preparation method and application thereof

CN121974907ACN 121974907 ACN121974907 ACN 121974907ACN-121974907-A

Abstract

The invention discloses PROTAC compounds for degrading TRIM15 protein, which have a structure shown in a formula (I). The molecule can effectively inhibit RIG-1 signal path, and has application prospect in preparing anti-inflammatory or autoimmune disease drugs. Meanwhile, the invention also provides a chemical probe molecule with the structure shown in the formula (III). One end of the molecule binds to TRIM15, and the other end can bind to a tag protein (such as Halo-tag) or other target protein, so that the TRIM15 is recruited as E3 ubiquitin ligase to perform ubiquitination modification on the tag protein (or target protein). The molecule can be used as an innovative research tool for exploring the biological functions, substrate specificity and non-K48 type ubiquitination modification of the E3 ligase of TRIM 15.

Inventors

  • ZHU CHENGLIANG
  • CAO JI
  • Shou Binyan
  • JIANG LI
  • YANG BO
  • QI XUXIN
  • WANG ZIDONG

Assignees

  • 浙江大学

Dates

Publication Date
20260505
Application Date
20251216

Claims (11)

  1. 1. A compound targeting TRIM15 protein, characterized by having a structure represented by formula (I): ; Or an optical isomer of the structure shown in formula (I) or a pharmaceutically acceptable salt thereof; in formula (I): L is selected from-L 1 -Linker-E3 Ligand、COOR 11 、-CONHR 22 , wherein R 11 is H or C1-C5 alkyl, R 22 is C1-C5 alkyl; the A ring is selected from 4-8 membered aromatic heterocycle, 5-8 membered aromatic heterocycle, 3-10 membered aliphatic heterocycle and 3-10 membered aliphatic ring which are substituted by one or more substituent groups, wherein the substituent groups are selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, carboxyl, hydroxyl, cyano, ester group and amido; l 1 is-CO-; Linker is a connecting group and is formed by combining one or more of straight chain or branched chain alkyl -(CH 2 ) n1 -、-(CH 2 O) n2 -、-NR 1 -、-(CH=CHCH 2 ) n3 -、-(C≡CCH 2 ) n4 -、3-8 -membered aliphatic ring, 3-8-membered aliphatic heterocyclic ring, spiro ring, 5-8-membered aromatic ring, 4-8-membered aromatic heterocyclic ring, - (CH 2 ) n5 CONH(CH 2 ) n6 -; Wherein n 1-n 6 each independently represents a natural number of 1-30, R 1 is H or C1-C10 alkyl, the spiro ring is a structure in which two ring systems are connected through a common atom, wherein the two rings are each independently selected from 3-8 membered aliphatic rings or aliphatic heterocyclic rings; E3 Ligand is an E3 ligase Ligand; The ester group is-COORaa, -OCORaa, and Raa is selected from C1-C3 alkyl; The amide group is-CONHRaa, -NHCORaa, and Raa is selected from C1-C3 alkyl.
  2. 2. The compound of claim 1, wherein the a ring is selected from the following structures: ; Wherein, the R A is selected from halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C5 alkoxy, carboxyl, hydroxyl, ester group, amide group and cyano, wherein the ester group is-COORaa, -OCORaa, raa is selected from C1-C3 alkyl, the amide group is-CONHRaa, -NHCORaa, and Raa is selected from C1-C3 alkyl; X is selected from C, CH and N; Y is selected from O, S; Linker is selected from the following structures: ; In the structure, n represents a natural number of 1-20, X 1 、X 2 、Y 1 、Y 2 is independently selected from N, CH, Z is selected from CH 2 and O, C =O; E3 The bond is selected from the following structures: Wherein M is c=o or CH 2 .
  3. 3. A compound according to claim 1 or 2, wherein the a ring has the structure: ; Linker is selected from the following structures: ; E3 The bond is selected from the following structures: 。
  4. 4. The compound according to claim 1, characterized in that it is selected from the following compounds: Or an optical isomer of the structure shown or a pharmaceutically acceptable salt thereof.
  5. 5. A pharmaceutical composition comprising a compound or prodrug according to any one of claims 1 to 4.
  6. 6. Use of a compound according to any one of claims 1-4 or a pharmaceutical composition according to claim 5 in any one of the following applications: when L is selected from-L 1 -Linker-E3 Ligand, the application is one of the following: (1) The application of the TRIM15 protein in preparing medicaments for inhibiting RIG-1 signal paths by degrading the TRIM15 protein; (2) As a research tool probe, the probe is used for exploring the application of the TRIM15 protein biological function; The L is selected from COOR 11 、-CONHR 22 , wherein R 11 is H or C1-C5 alkyl, and R 22 is C1-C5 alkyl, and the application of the L is the application of the L serving as a TRIM15 targeting ligand in preparing a bifunctional compound targeting TRIM15 protein.
  7. 7. A compound characterized by having a structure represented by formula (II) or an optical isomer having a structure represented by formula (II) or a pharmaceutically acceptable salt thereof: ; Wherein ring a is as defined in claim 1, 2 or 3; l 1 is-CO-; Linker is as defined in claim 1, 2 or 3; POI is a chemical group selected from the following structures: or C4-C10 haloalkanes.
  8. 8. The compound of claim 7, wherein POI is selected from C5-C7 chlorinated alkane compounds, linker is selected from-NHCH 2 (CH 2 OCH 2 ) n CH 2 O-, and n is 1,2,3,4.
  9. 9. The compound of claim 7, selected from the group consisting of: 。
  10. 10. A pharmaceutical composition characterized by comprising a compound according to any one of claims 7 to 9, an isomer thereof, a pharmaceutically acceptable salt or prodrug thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.
  11. 11. Use of a compound according to any one of claims 7 to 9, or a pharmaceutical composition according to claim 10, for (1) the use of said compound in the preparation of a research tool probe for studying TRIM15 protein E3 ubiquitin ligase activity, (2) the use of said compound in the preparation of a kit for recruiting TRIM15 protein ubiquitination of a target substrate.

Description

TRIM 15-targeted small molecule conjugate and preparation method and application thereof Technical Field The invention belongs to the fields of pharmaceutical chemistry and chemical biology, and particularly relates to a novel compound targeting TRIM15 protein, and a preparation method and application of the novel compound serving as a protein degradation agent and/or an E3 ligase activity research probe. Background The triple motif (TRIPARTITE MOTIF, TRIM) protein family contains eighty members in the human genome and is widely involved in a variety of key life processes such as cell proliferation, differentiation, apoptosis, tumorigenesis, innate immunity, and the like. TRIM15, as a member of this family, has its N-terminal Ring domain conferring E3 ubiquitin ligase activity. Recent studies have shown that TRIM15 plays an important role in a variety of diseases. On one hand, it is remarkably up-regulated in various cancers such as melanoma, non-small cell lung cancer and the like and promotes proliferation and metastasis of cancer cells, and on the other hand, TRIM15 is also a key driving factor for osteoarthritis and is involved in regulating inflammation and innate immune signals. In particular, TRIM15 has been shown to be a key regulator of the RIG-1-MAVS signaling pathway. Excessive activation of the pathway is causative of various autoimmune diseases, and silencing TRIM15 by genetic means can significantly inhibit secretion of type I interferon downstream of the signal pathway, indicating that TRIM15 is a potential anti-inflammatory and important target for treating autoimmune diseases. In view of the key roles of TRIM15 in tumorigenesis and inflammatory signaling pathways, the development of small molecule compounds capable of specifically regulating their biological activities has become a key scientific problem in solving the treatment problems of related diseases. However, the current intervention strategies for TRIM15 are still limited to genetic means such as gene knockout or RNA interference, and no specific small molecule inhibitors or modulators have been reported. Therefore, there is an urgent need in the art for two innovative tools, namely, one capable of degrading small molecules of TRIM15 protein with high efficiency and specificity for treating related diseases driven by the dysfunction of TRIM15, and the other capable of using chemical probes of the E3 ligase activity of TRIM15 with specificity for in-depth research of its catalytic mechanism, substrate recognition and complex functions in cell signaling pathway. Disclosure of Invention The invention aims to solve the technical problems and provide a target TRIM15 protein bifunctional compound based on the same core structure skeleton and application thereof. Based on the newly discovered TRIM15 small molecule ligand, two types of molecular entities with different functions are developed: The first is a proteolytically targeted chimeric (PROTAC) molecule that is capable of achieving efficient, specific degradation of TRIM15 proteins by recruiting the cell's endogenous E3 ubiquitin ligase. The molecules can effectively down regulate the level of TRIM15 protein, thereby inhibiting the excessive activation of RIG-1 signal channels, and showing great application prospects in the aspect of developing novel anti-inflammatory or autoimmune disease treatment medicines. The second class is the TRIM15 recruitment molecule, which can serve as a chemobiological research probe. One end of the molecule is specifically combined with TRIM15, and the other end of the molecule is coupled with target protein (such as fusion protein with a Halo-tag and other report labels) through a specific target protein binding ligand (such as halogenated alkane), so that the E3 ligase activity of the TRIM15 is guided to the target protein, and the specific ubiquitination modification of the target protein is realized. Such molecules provide innovative tools for studying the E3 ligase activity, substrate specificity, and biological function of the nondegradable ubiquitinated signal chain of TRIM 15. In order to achieve the dual purposes, the invention provides the following technical scheme: a compound targeting TRIM15 protein, which has the structure shown in the following formula (I): L is selected from-L 1-Linker-E3 Ligand 、COOR11、-CONHR22, wherein R 11 is H or C1-C5 alkyl, and R 22 is C1-C5 alkyl. In a first aspect of the present invention, formula (I), wherein L is selected from the group consisting of-L 1 -Linker-E3 Ligand, the present invention provides a PROTAC compound having the structure of formula (I-1), an optical isomer thereof, and a pharmaceutically acceptable salt thereof: in formula (I) or formula (I-1): The A ring is selected from one or more substituted 4-8 membered aromatic heterocycle, 5-8 membered aromatic heterocycle, 3-10 membered aliphatic heterocycle and 3-10 membered aliphatic ring, wherein the substituent is selected from halogen, C1-C3 al