2. Academic Validation
  3. Discovery of a Highly Potent and Selective Degrader Targeting Hematopoietic Prostaglandin D Synthase via In Silico Design

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

  • J Med Chem. 2021 Nov 11;64(21):15868-15882. doi: 10.1021/acs.jmedchem.1c01206.
Hidetomo Yokoo 1,  Norihito Shibata 2,  Akinori Endo 3,  Takahito Ito 1,  Yuta Yanase 1 4,  Yuki Murakami 1 4,  Kiyonaga Fujii 5,  Kengo Hamamura 6,  Yasushi Saeki 3,  Mikihiko Naito 7,  Kosuke Aritake 6,  Yosuke Demizu 1 4
Affiliations

Affiliations

  • 1 Division of Organic Chemistry, National Institute of Health Sciences, 3-25-26 Tonomachi, Kawasaki-ku, Kawasaki-shi, Kanagawa 210-9501, Japan.
  • 2 Division of Biochemistry, National Institute of Health Sciences, 3-25-26 Tonomachi, Kawasaki-ku, Kawasaki-shi, Kanagawa 210-9501, Japan.
  • 3 Protein Metabolism Project, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo 156-8506, Japan.
  • 4 Graduate School of Medical Life Science, Yokohama City University, 1-7-29 Suehirocho, Tsurumi-ku, Yokohama-shi, Kanagawa 230-0045, Japan.
  • 5 Laboratory of Analytical Chemistry, Daiichi University of Pharmacy, 22-1 Tamagawa-machi, Minami-ku, Fukuoka-shi, Fukuoka 815-8511, Japan.
  • 6 Laboratory of Chemical Pharmacology, Daiichi University of Pharmacy, 22-1 Tamagawa-machi, Minami-ku, Fukuoka-shi, Fukuoka 815-8511, Japan.
  • 7 Laboratory of Targeted Protein Degradation, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
PMID: 34652145 DOI: 10.1021/acs.jmedchem.1c01206
Abstract

Targeted protein degradation by proteolysis-targeting chimera (PROTAC) is one of the exciting modalities for drug discovery and biological discovery. It is important to select an appropriate linker, an E3 Ligase ligand, and a target protein ligand in the development; however, it is necessary to synthesize a large number of PROTACs through trial and error. Herein, using a docking simulation of the ternary complex of a hematopoietic prostaglandin D synthase (H-PGDS) degrader, H-PGDS, and Cereblon, we have succeeded in developing PROTAC(H-PGDS)-7 (6), which showed potent and selective degradation activity (DC50 = 17.3 pM) and potent suppression of prostaglandin D2 production in KU812 cells. Additionally, in a Duchenne muscular dystrophy model using mdx mice with cardiac hypertrophy, compound 6 showed better inhibition of inflammatory cytokines than a potent H-PGDS inhibitor TFC-007. Thus, our results demonstrated that in silico simulation would be useful for the rational development of PROTACs.

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