Discovery of a Highly Potent and Selective Degrader Targeting Hematopoietic Prostaglandin D Synthase via in Silico Design


Hematopoietic prostaglandin D synthase (H-PGDS) is an attractive target for the development of therapeutic agents for Duchenne muscular dystrophy (DMD) and other H-PGDS-related diseases. We have recently developed the H-PGDS degrader PROTAC(H-PGDS)-1, which is a chimeric molecule in which TFC-007 (that binds to H-PGDS) and pomalidomide (that binds to cereblon [CRBN]) were conjugated to the PEG5 linker. Herein, using a docking simulation of the ternary complex of the H-PGDS degrader, H-PGDS, and CRBN, we have succeeded in developing PROTAC(H-PGDS)-7, a new H-PGDS degrader that does not contain a linker. PROTAC(H-PGDS)-7 showed potent and selective degradation activity (DC50 = 17.3 pM), and potent suppression of prostaglandin D2 (PGD2) production in KU812 cells. Additionally, in a DMD model using mdxmice with cardiac hypertrophy, PROTAC(H-PGDS)-7 showed better inhibition of inflammatory cytokines than TFC-007. PROTAC(H-PGDS)-7 is expected to be a promising candidate for the treatment of DMD and other H-PGDS-related diseases.


Supplementary material

Extended Data Fig.1
Extended Data Fig.2
Extended Data Fig.3
Extended Data Fig.4
Extended Data Fig.5
Extended Data Fig.6
Extended Data Fig.7
Extended Data Fig.8
Extended Data Fig.9
Extended Data Fig.10
Figure 1
Figure 2v3
Figure 3v5
Figure 4v5
Figure 5v3
Figure 6v2
Source Data Extended Data Fig.4,5,8
Source Data Extended Data Fig.9, 10
Source data Fig.2a
Source Data Fig.2b,c
Source Data Fig.3a,b,d,e
20210606 SI