2. Academic Validation
  3. Alkyne Two-Phase Strategy: Rapid Generation of TK-285-Derived PROTACs as BRD4 Degraders

Alkyne Two-Phase Strategy: Rapid Generation of TK-285-Derived PROTACs as BRD4 Degraders

  • J Med Chem. 2026 Apr 9;69(7):8388-8416. doi: 10.1021/acs.jmedchem.5c03771.
Hiroyuki Yamakoshi 1,  Ryo Watanabe 1,  Ryosuke Segawa 1 2,  Ryosuke Ishihara 1,  Ryo Tachibana 1,  Genki Kudo 3,  Shota Nagasawa 1,  Satoshi Yamanaka 4,  Ayano Ito 1,  Hiroyuki Takeda 5,  Tatsuya Sawasaki 6,  Ryunosuke Yoshino 7 8,  Takatsugu Hirokawa 7 8,  Takayuki Doi 1,  Noriyasu Hirasawa 1,  Yoshiharu Iwabuchi 1
Affiliations

Affiliations

  • 1 Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aoba, Aramaki, Aoba-ku, Sendai 980-8578, Japan.
  • 2 Department of Pharmaceutical Sciences, Tohoku University Hospital, Sendai 980-8574, Japan.
  • 3 Graduate School of Pure and Applied Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8577, Japan.
  • 4 Division of Proteo-Interactome, Proteo-Science Center, Ehime University, 3 Bunkyo-cho, Matsuyama, Ehime 790-8577, Japan.
  • 5 Division of Proteo-Drug-Discovery Sciences, Proteo-Science Center, Ehime University, 3 Bunkyo-cho, Matsuyama, Ehime 790-8577, Japan.
  • 6 Division of Cell-Free Sciences, Proteo-Science Center, Ehime University, 3 Bunkyo-cho, Matsuyama, Ehime 790-8577, Japan.
  • 7 Institute of Medicine, University of Tsukuba, 2 Amakubo, Tsukuba, Ibaraki 305-0005, Japan.
  • 8 Transborder Medical Research Center, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8577, Japan.
PMID: 41852276 DOI: 10.1021/acs.jmedchem.5c03771
Abstract

This study introduces a divergent synthetic strategy in linkerology using preassembled linkers to generate structural diversity. The approach was validated by developing bromodomain-containing protein 4 (BRD4)-targeting proteolysis-targeting chimeras (PROTACs) based on an "alkyne two-phase strategy," employing the BRD4 Inhibitor TK-285 as the binding ligand. In the initial screening phase, alkyne-modified TK-285 derivatives were subjected to click chemistry to optimize linker length and the modification site, leading to the identification of TKP-5 as a potent degrader. TKP-5 exhibited stronger thymic stromal lymphopoietin─more suppressive activity than TK-285 and markedly suppressed IL-33 mRNA expression in a tape-stripping-induced skin injury model. In the subsequent optimization phase, late-stage diversification using 1,3-butadiyne-typed PROTAC intermediates revealed the critical contribution of the triazole moiety, supported by in silico analysis suggesting interaction with Trp81 of BRD4. The strategy is expected to be broadly applicable to modular Functional Molecules accessible via click chemistry.

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