Unraveling the therapeutic landscape of approved non-peptide macrocycles

Abstract

Non-peptide macrocyclic drugs possess unique structural advantages that allow them to target various biomolecules of interest and thus show therapeutic potential against various diseases such as cancer, infectious diseases, etc. This review article examines 34 non-peptide macrocyclic drugs approved between 2000 and 2024, with a particular focus on the optimization process of representative macrocyclic drugs such as natural macrocycles, natural product-inspired macrocycles, and de novo-designed macrocycles. We discuss their structural characteristics, highlighting how conformational rigidity and enhanced target specificity contribute to their efficacy. Design details of these new macrocyclic drugs are illustrated through successful examples, offering insights for optimizing macrocycles. Of note, macrocyclization of U-shaped lead structures represents a novel molecular skeleton editing strategy in de novo macrocycle drug design.

Keywords: Drug discovery; Macrocycles; Macrocyclization; Molecular editing; Non-peptides.

Graphical abstract

Figure 1

An overview of approved from 2000 to 2024. (A) Annual numbers of approved non-peptide macrocycles and small molecules; Macrocyclic drugs classified by therapeutic indications (B) and origins (C).

Figure 2

Examples of approved natural non-peptide macrocyclic drugs.

Figure 3

Fidaxomicin and its complex structure with Cdiff Eσ^A (PDB: 7L7B). 3D visualizations were performed using PyMOL (Pymol.org).

Figure 4

Chemical structure and discovery of eribulin via simplification of halichondrin B.

Figure 5

Chemical structures and discovery of pimecrolimus (A) and moxidectin (B).

Figure 6

(A) Design strategy for ixabepilone based on epothilone B; (B) Comparison of the active site overlap between ixabepilone (PDB: 7DAF, shown in green) and epothilone B (PDB: 7DAE, shown in cyan) on Tubulin. (C) Analysis of the binding interaction between ixabepilone and Tubulin. Hydrogen bonds are highlighted in red dash lines. MDR (IC₅₀ R/S), the ratio of IC₅₀ values in MDR resistant versus sensitive cell lines. 3D visualizations were performed using PyMOL (Pymol.org).

Figure 7

Chemical structure and discovery of telithromycin derived from erythromycin.

Figure 8

Structures of rapamycin and its analogs including zotarolimus, everolimus, and temsirolimus. The interaction of rapamycin with FKBP12 and mTOR (PDB: 1FAP) is indicated. 3D visualizations were performed using PyMOL (Pymol.org).

Figure 9

Chemical structure and discovery of simeprevir. The section marked with the green sphere represents the two points where they connect to form a ring.

Figure 10

Design strategy of danoprevir and its interactions with wild-type (PDB: 3M5L) and A156T (PDB: 3SU2) NS3/4A proteases. Danoprevir is highlighted in green and purple sticks, respectively. The section marked with the green sphere represents the two points where they connect to form a ring. Hydrogen bonds are highlighted in red dash lines. 3D visualizations were performed using PyMOL (Pymol.org).

Figure 11

Chemical structure and discovery of paritaprevir.

Figure 12

Chemical structure and design strategy of vaniprevir. 3D visualizations of NS3/4A protease (PDB: 5ESB) were performed using PyMOL (Pymol.org).

Figure 13

Chemical structures and design strategy of grazoprevir, voxilaprevir, glecaprevir.

Figure 14

Chemical structure and design strategy of pacritinib. The diagrams illustrate the interaction between pacritinib (highlighted in green) and JAK2 (PDB: 8BPV), as well as the overlap of compound J (highlighted in red). Hydrogen bonds are highlighted in red dash lines. 3D visualizations were performed using PyMOL (Pymol.org).

Figure 15

Chemical structure and design strategy of icotinib. The docking diagram illustrates the overlap of icotinib (highlighted in green) and erlotinib (highlighted in cyan) with EGFR (PDB: 4HJO). Hydrogen bonds are highlighted in red dash lines. 3D visualizations were performed using PyMOL (Pymol.org).

Figure 16

Chemical structures and design strategy of lorlatinib and repotrectinib. The binding diagrams display lorlatinib (green sticks) and crizotinib (cyan sticks) bound to ALK (PDB: 4CLI), as well as repotrectinib (green sticks) and crizotinib (cyan sticks) bound to ROS1 (PDB: 4XUL). Hydrogen bonds are highlighted in red dash lines. 3D visualizations were performed using PyMOL (Pymol.org).

Figure 17

Chemical structure and development of plerixafor derived from JM1498 (A) and the crystal structures of CXCR4 (PDB: 8U4P) with plerixafor. Hydrogen bonds are highlighted in red dash lines. 3D visualizations were performed using PyMOL (Pymol.org).