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[Preprint]. 2024 Aug 7:rs.3.rs-4730282.
doi: 10.21203/rs.3.rs-4730282/v1.

Structural Study of Selectivity Mechanisms for JNK3 and p38α with Indazole Scaffold Probing Compounds

HaJeung Park  1 , Yangbo Feng  2
Affiliations

Structural Study of Selectivity Mechanisms for JNK3 and p38α with Indazole Scaffold Probing Compounds

HaJeung Park et al. Res Sq. .

Abstract

Selectivity is a primary focus in medicinal chemistry for ATP-competitive kinase inhibitors due to the highly conserved ATP binding pockets in the kinome. A decade of medicinal chemistry efforts has been carried out to develop selective inhibitors for JNKs, resulting in the identification of numerous promising scaffolds that even exhibit isoform selectivity. Thiophene-indazole is one of the scaffolds explored for isoform selectivity. Some iterations of this scaffold have also shown selectivity for p38α. In this study, we utilized four compounds derived from thiophene-indazole to investigate the mechanisms of selectivity for JNK3 and p38α. We determined crystal structures of the inhibitors bound to either JNK3 or p38α and subjected them to molecular dynamics (MD) simulations to understand the binding mechanism and critical interactions that govern affinity and selectivity for these two important kinases. The findings from this study provides valuable information for improving current lead inhibitors and developing a new generation of JNK3 isoform inhibitors.

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Figures

Figure 1
Figure 1
The pyrazole-urea scaffold (Inhibitor 1) and strategies for further optimization led to the development of thiophene pyrazole-urea (Inhibitor 2) and thiophene-indazole (Inhibitor 3).
Figure 2
Figure 2
Superposition of JNK3 complexes. A, The interaction of the ligand with the hydrophobic pocket of JNK3 is illustrated using JNK3:21J as the representative example. The key hydrophobic residues are shown as sticks with transparent spheres, and the ligand is shown as sticks. B and C, The conformational differences between JNK3:21M and the rest of the complexes are clearly shown in the overlaps. The side chain of Met146 occupies the void produced by the rotation of the methoxy phenyl ring. The conformation affords cation-π interaction between Lys93 and 21M. The conserved H-bond interactions between the hinge residue, Met149, and the bound inhibitors are indicated with yellow dashed lines. The bound inhibitors and the corresponding residues are colored green, cyan, orange, and blue for 21J, 21G, 23M, and 23GA, respectively.
Figure 3
Figure 3
Structural comparison of p38α:21G and p38α:21J at the hydrophobic interface. The N-methyl azetidine substitution at C6 of indazole in 21G demonstrates superior VdW interaction with both Tyr35 and Leu167 compared to the dimethyl ether substitution in 21J. The black arrow indicates the VdW void in the p38α:21J complex. The key residues and the compounds are depicted as sticks with transparent spheres, and the key residues are labeled.
Figure 4
Figure 4
Comparison of the key water-mediated H-bond interactions. Three significant water-mediated H-bond interactions are observed in both JNK3:21J and JNK3:21G. The primary difference lies in the H-bond interaction mediated by Asn152, where the rotation of the side chain is locked in by Ser193.
Figure 5
Figure 5
Comparison of the VdW interface between p38α:23M and p38α:23GA. The key residues surrounding the C4 of thiophene where methyl substitution occurs in 23G are shown in spheres. The VdW interface in the p38α:23GA complex is tightly filled compared to that of p38α:23M due to the addition of a methyl group, which enhances hydrophobic interaction.
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