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CN-121991032-A - NAMPT and HDAC double-target protein degradation agent and application thereof

CN121991032ACN 121991032 ACN121991032 ACN 121991032ACN-121991032-A

Abstract

The invention discloses a NAMPT and HDAC double-target protein degradation agent or a medicinal salt thereof, and the structural general formula is selected from one of the following structures: Preliminary activity tests were performed on NAMPT series and HDAC series. The results show that of all the tested compounds, compound N4 and compound H4 exhibited significant degradation effects. The compound provided by the invention can be applied to preparing synergistic degradation agents targeting NAMPT and HDAC.

Inventors

  • WANG WEI
  • SHENG CHUNQUAN
  • YANG CHANGLING
  • Bao Yuhan
  • DONG GUOQIANG

Assignees

  • 中国人民解放军海军军医大学

Dates

Publication Date
20260508
Application Date
20260130

Claims (9)

  1. 1. A NAMPT and HDAC dual-target protein degrading agent or a pharmaceutically acceptable salt thereof, characterized by a general structural formula selected from one of the following structures: ; the general formula H and the general formula C are combined to serve as NAMPT and HDAC double-target protein degradation agents, or the general formula N and the general formula C are combined to serve as NAMPT and HDAC double-target protein degradation agents, Or, formula N and formula H in combination with formula C as NAMPT and HDAC dual target protein degrading agents; Wherein, the R 1 is selected from ; R 4 is selected from C3-C10 naphthene radicals; n1 is a positive integer from 1 to 5; r 5 is selected from C3-C10 cycloalkanyloxy group, ; N2 is a positive integer from 1 to 5; r 6 is selected from C3-C10 cycloalkanyloxy group, ; R 7 is selected from hydrogen and C1-C10 alkyl; L is selected from- (CH 2 )n3、-(CH 2 )n4CONH(CH 2 ) n5-; n3 is a positive integer from 1 to 20; n4 is a positive integer from 1 to 20; n5 is a positive integer from 1 to 20; R 2 is selected from C3-C10 cycloalkanyloxy group, ; N6 is a positive integer from 1 to 10; R 3 is selected from 。
  2. 2. The NAMPT and HDAC dual-target protein degradation agent or a pharmaceutically acceptable salt thereof according to claim 1, wherein, in said NAMPT and HDAC dual-target protein degradation agent, R 1 is selected from ; R 4 is selected from ; N1 is selected from 1,2, 3, 4, 5; r 5 is selected from ; N2 is selected from 1,2, 3, 4, 5; R 6 is selected from ; L is selected from- (CH 2 )n3、-(CH 2 )n4CONH(CH 2 ) n5-; n3 is selected from 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12; n4 is selected from 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12; n5 is selected from 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12; r 2 is selected from ; N6 is selected from 1,2,3,4,5, 9, 7, 8, 9; R 3 is selected from 。
  3. 3. The NAMPT and HDAC dual-target protein degradation agent or a pharmaceutically acceptable salt thereof according to claim 2, wherein the structure of said NAMPT and HDAC dual-target protein degradation agent is selected from one of the following structures: 。
  4. 4. Use of a NAMPT and HDAC dual target protein degradation agent as claimed in any one of claims 1 to 3 in the manufacture of a medicament for the treatment of breast cancer.
  5. 5. Use of a NAMPT and HDAC dual-target protein degradation agent as claimed in any one of claims 1 to 3 in the preparation of a NAMPT and HDAC dual-target protein degradation agent.
  6. 6. Use of a compound N4 according to claim 3 in combination with compound C2 for the preparation of a NAMPT and HDAC dual target protein degradation agent.
  7. 7. Use of compound H4 as claimed in claim 3 in combination with compound C2 for the preparation of NAMPT and HDAC dual target protein degrading agents.
  8. 8. Use of compound H4 and compound N4 in combination with compound C2 according to claim 3 for the preparation of NAMPT and HDAC dual target protein degrading agents.
  9. 9. Use of compound H4 and compound N4 in combination with compound C2 or compound H4 in combination with compound C2 in the manufacture of a medicament for the treatment of breast cancer.

Description

NAMPT and HDAC double-target protein degradation agent and application thereof Technical Field The invention belongs to the technical field of medicine preparation, and particularly relates to a NAMPT and HDAC double-target protein degradation agent and application thereof. Background Traditional drug development has long followed a "single target" strategy, i.e., designing highly selective molecules to accurately inhibit a single disease-associated protein. Although the mode has remarkable results, the curative effect is limited in multi-factor complex diseases such as cancers due to redundant signal paths. Therefore, a "multi-target" strategy that is capable of simultaneously intervening multiple key targets is an important development direction, where protein degradation targeting chimeric technologies are of great interest because of their advantage of being able to target "non-patent" proteins. However, the limitations of large molecular weight and poor membrane permeability of the conventional PROTAC as a single heterobifunctional macromolecule generally limit the further development of the single heterobifunctional macromolecule, and especially the design of multi-target degradants faces more challenges due to the increase of molecular complexity. In recent years, the rise of bio-orthogonal chemistry provides an innovative idea for breaking through the bottleneck. The technology can perform efficient and specific chemical reactions in living cells without disturbing normal physiological processes. In particular, based on the inverse electron demand diels-alder reaction of trans-cyclooctene and tetrazine, the complete PROTAC molecules can be split into two small molecule precursors with good cell permeability, so that the small molecule precursors are self-assembled in cells, and the physicochemical property defect of the traditional PROTAC is skillfully avoided. Disclosure of Invention The invention aims to provide NAMPT and HDAC double-target protein degradation agent. It is another object of the present invention to provide the use of said NAMPT and HDAC dual target protein degradation agents for the preparation of a medicament for the treatment of breast cancer. In order to achieve the above purpose, the technical scheme adopted by the invention is as follows: in a first aspect of the present invention, there is provided a NAMPT and HDAC dual target protein degrading agent or a pharmaceutically acceptable salt thereof, having a general structural formula selected from one of the following structures: ; the general formula H and the general formula C are combined to serve as NAMPT and HDAC double-target protein degradation agents, or the general formula N and the general formula C are combined to serve as NAMPT and HDAC double-target protein degradation agents, Or, formula N and formula H in combination with formula C as NAMPT and HDAC dual target protein degrading agents; Wherein, the R 1 is selected from ; R 4 is selected from C3-C10 naphthene radicals; n1 is a positive integer from 1 to 5 (e.g., 1, 2, 3, 4, 5); r 5 is selected from C3-C10 cycloalkanyloxy group, ; N2 is a positive integer from 1 to 5 (e.g., 1, 2, 3, 4, 5); r 6 is selected from C3-C10 cycloalkanyloxy group, ; R 7 is selected from hydrogen and C1-C10 alkyl; L is selected from- (CH 2)n3、-(CH2)n4CONH(CH2) n5-; n3 is selected from positive integers of 1 to 20 (e.g. 1, 2,3, 4, 5, 6,7, 8, 9, 10, 11, 12); n4 is selected from positive integers of 1 to 20 (e.g. 1, 2,3, 4, 5, 6,7, 8, 9, 10, 11, 12); n5 is selected from positive integers of 1 to 20 (e.g. 1, 2,3, 4, 5, 6,7, 8, 9, 10, 11, 12); R 2 is selected from C3-C10 cycloalkanyloxy group, ; N6 is selected from positive integers of 1 to 10 (e.g. 1, 2, 3, 4, 5, 9, 7, 8, 9); R 3 is selected from 。 More preferably, in the NAMPT and HDAC dual target protein degradation agent, Wherein, the R 1 is selected from ; R 4 is selected from; N1 is selected from 1,2, 3, 4, 5; r 5 is selected from ; N2 is selected from 1,2, 3, 4, 5; R 6 is selected from ; L is selected from- (CH 2)n3、-(CH2)n4CONH(CH2) n5-; n3 is selected from 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12; n4 is selected from 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12; n5 is selected from 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12; r 2 is selected from ; N6 is selected from 1,2,3,4,5, 9, 7, 8, 9; R 3 is selected from 。 Most preferably, the structures of the NAMPT and HDAC dual target protein degrading agent are selected from one of the following structures: 。 In a second aspect, the invention provides an application of the NAMPT and HDAC double-target protein degradation agent in preparing a medicament for treating breast cancer. In a third aspect of the invention, there is provided an application of the NAMPT and HDAC double-target protein degradation agent in preparing NAMPT and HDAC double-target protein degradation agent. In a fourth aspect of the invention, there is provided the use of a compound N4 in combination with a compound C2 for the preparation o