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A "Ligand First" Approach toward Selective, Covalent JNK2/3 Inhibitors.

Valentin R Wydra1, Nicole Plank2, Stefan Zwirner3

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Researchers developed novel JNK2/3 selective inhibitors. These compounds, both reversible and covalent, show high potency and cellular activity, with a lead covalent compound demonstrating excellent kinetic and selectivity profiles.

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Area of Science:

  • Biochemistry
  • Medicinal Chemistry
  • Pharmacology

Background:

  • JNK isoforms (JNK1, JNK2, JNK3) have distinct roles in diseases.
  • JNK2 has been less studied than JNK1 and JNK3.
  • JNK3 is a target for neurodegenerative diseases, and JNK1 inhibitors are in clinical trials.

Purpose of the Study:

  • To develop novel, highly potent, and isoform-selective JNK2/3 inhibitors.
  • To explore both reversible and covalent inhibitor strategies.
  • To identify a lead compound with favorable kinetic and selectivity properties.

Main Methods:

  • Structure-guided optimization of an aminopyrazole scaffold.
  • Iterative ligand-first approach for inhibitor design.
  • Transformation of reversible inhibitors into covalent inhibitors using electrophilic warheads targeting a conserved cysteine.

Main Results:

  • Generation of novel, potent JNK2/3 selective reversible and covalent inhibitors.
  • Demonstrated high isoform selectivity and cellular activity for both inhibitor types.
  • The lead covalent compound 56d exhibited potent inhibition (k_inact/K_I = 38,200 M^-1 s^-1 for JNK2), cellular selectivity, and a clean kinome profile.

Conclusions:

  • Successfully developed potent and selective JNK2/3 inhibitors using a structure-guided approach.
  • Covalent inhibitors targeting conserved cysteines represent a promising strategy for JNK2/3 inhibition.
  • Lead compound 56d shows potential for further therapeutic development, particularly for diseases involving JNK2/3 dysregulation.