2. Academic Validation
  3. Correlation between tight binding of inhibitors and their target selectivity toward the non-native state in the DYRK family of kinases

Correlation between tight binding of inhibitors and their target selectivity toward the non-native state in the DYRK family of kinases

  • Bioorg Med Chem Lett. 2026 Apr:133:130527. doi: 10.1016/j.bmcl.2025.130527.
Natsumi Yamada 1,  Sora Suzuki 2,  Nanae Fukahori 3,  Yoshiyuki Yamaoka 4,  Yuta Komiyama 3,  Ninako Kimura 3,  Koji Umezawa 4,  Isao Kii 5
Affiliations

Affiliations

  • 1 Laboratory for Drug Target Research, Integrated Bioscience Division, Department of Agriculture, Graduate School of Science and Technology, Shinshu University, 8304 Minami-Minowa, Kami-Ina, Nagano 399-4598, Japan.
  • 2 Laboratory for Drug Target Research, Integrated Bioscience Unit, Biological and Agricultural Sciences Division, Department of Science and Technology, Graduate School of Medicine, Science and Technology, Shinshu University, 8304 Minami-Minowa, Kami-Ina, Nagano 399-4598, Japan.
  • 3 Laboratory for Drug Target Research, Division of Life and Food Science, Faculty of Agriculture, Shinshu University, 8304 Minami-Minowa, Kami-Ina, Nagano 399-4598, Japan.
  • 4 Laboratory of Functional Molecular Design, Division of Life and Food Science, Faculty of Agriculture, Shinshu University, 8304 Minami-Minowa, Kami-Ina, Nagano 399-4598, Japan.
  • 5 Laboratory for Drug Target Research, Integrated Bioscience Division, Department of Agriculture, Graduate School of Science and Technology, Shinshu University, 8304 Minami-Minowa, Kami-Ina, Nagano 399-4598, Japan; Laboratory for Drug Target Research, Integrated Bioscience Unit, Biological and Agricultural Sciences Division, Department of Science and Technology, Graduate School of Medicine, Science and Technology, Shinshu University, 8304 Minami-Minowa, Kami-Ina, Nagano 399-4598, Japan; Laboratory for Drug Target Research, Division of Life and Food Science, Faculty of Agriculture, Shinshu University, 8304 Minami-Minowa, Kami-Ina, Nagano 399-4598, Japan. Electronic address: [email protected].
PMID: 41461351 DOI: 10.1016/j.bmcl.2025.130527
Abstract

A folding intermediate of dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) in the non-native state autophosphorylates intramolecularly, whereas the folded conformation of DYRK1A in the native state no longer catalyzes this reaction. We identified FINDY, a small molecule that selectively inhibits the DYRK1A folding intermediate but not its fully folded conformation. These findings indicated the presence of a unique binding site that is exposed only in the folding intermediate. In the previous study, we developed a facile method for screening of inhibitors that target the folding intermediate in the non-native state using recombinant folded proteins in the native state. We found that FINDY and its derivatives target both DYRK1A and DYRK1B in their non-native states. In this study, we examined the potency of these inhibitors on DYRK2, another member of the DYRK family. FINDY inhibited DYRK2 in the non-native state slightly greater than that in the native state. Although RD0448, a FINDY derivative, selectively targets DYRK1A/1B in their non-native states, RD0448 exhibited no selectivity between the native and non-native states of DYRK2, indicating that the RD0448-binding site is hidden in the native state of DYRK1A/1B but is exposed in the native state of DYRK2. Furthermore, RD0448 bound tightly to DYRK1A/1B, whereas RD0448 showed weak affinity for DYRK2 and rapidly dissociated from the binding complex. These results suggest a correlation between the tight binding of the inhibitors and their target selectivity toward the non-native state in DYRK family kinases.

Keywords

DYRK1A; DYRK1B; DYRK2; Folding intermediate; Non-native state; Temperature vaulting.

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