IRAK-4 inhibitors for inflammation

Abstract

Interleukin-1 receptor-associated kinases (IRAKs) are key components in the signal transduction pathways utilized by interleukin-1 receptor (IL-1R), interleukin-18 receptor (IL-18R), and Toll-like receptors (TLRs). Out of four members in the mammalian IRAK family, IRAK-4 is considered to be the "master IRAK", the only family member indispensable for IL-1R/TLR signaling. In humans, mutations resulting in IRAK-4 deficiency have been linked to susceptibility to bacterial infections, especially recurrent pyogenic bacterial infections. Furthermore, knock-in experiments by several groups have clearly demonstrated that IRAK-4 requires its kinase activity for its function. Given the critical role of IRAK-4 in inflammatory processes, modulation of IRAK-4 kinase activity presents an attractive therapeutic approach for the treatment of immune and inflammatory diseases. The recent success in the determination of the 3-dimensional structure of the IRAK-4 kinase domain in complex with inhibitors has facilitated the understanding of the mechanistic role of IRAK-4 in immunity and inflammation as well as the development of specific IRAK-4 kinase inhibitors. In this article, we review the biological function of IRAK-4, the structural characteristics of the kinase domain, and the development of small molecule inhibitors targeting the kinase activity. We also review the key pharmacophores required for several classes of inhibitors as well as important features for optimal protein/inhibitor interactions. Lastly, we summarize how these insights can be translated into strategies to develop potent IRAK-4 inhibitors with desired properties as new anti-inflammatory therapeutic agents.

Fig. (1)

TIR signaling pathways. This figure illustrates that inhibition of IRAK-4 kinase activity should primarily block MyD88-dependent TLR signaling, resulting in induced AP-1 and NF-κB activation, while anti-viral responses should remain mainly intact.

Fig. (2)

Overall structure of the IRAK-4 kinase domain (PDB code: 2NRU).

Fig. (3)

Unique features of the IRAK-4 kinase domain. a) The Schellman loop in the N-terminal extension (shown in magenta) and the extra long loop αDE (shown in orange) extends the ATP-binding pocket (PDB code: 2NRU). b) Activation loop of IRAK-4 with its phosphate ligand binding interactions resembling that of protein tyrosine kinases (PDB code: 2OIB). c) The P+1 site of IRAK-4 with a conserved threonine residue in serine/threonine kinases, Thr315, interacting with the catalytic base Asp311 and Lys313 (PDB code: 2NRU). d) The substrate-binding area of IRAK-4, docked with a putative substrate peptide from the activation loop of IRAK-1 (shown in yellow sticks).

Fig. (4)

The gatekeeper region and the ATP-binding pocket of IRAK-4. a) The unique Tyr262 gatekeeper interacts with an absolutely conserved glutamate residue Glu233, disrupting the usual Glu-Lys salt bridge (PDB code: 2OIB). b) The ATP-binding site has no back pocket due to the tyrosine gatekeeper (PDB: 2OID).

Fig. (5)

The dual conformations of apo IRAK-4 (PDB code: 2OIB). a) Overall two conformations of IRAK-4. b) Two conformations differ mainly in the N-lobe where helix αC, the Gly-rich loop, and the N-terminal extension show evident movements. c) Two conformations are symbolized by “helix αC-in” and “helix αC-out” positions, where the invariant Glu233 shows different side chain conformations. d) The usual Glu-Lys salt bridge is observed only in the “helix αC-out” conformation.

Fig. (6)

Chemical structures of representative IRAK-4 inhibitors discovered through medicinal chemistry efforts.

Fig. (7)

Initial IRAK-4 inhibitor hits from an aminobenzimidazole series.

Fig. (8)

Inhibitor compound 1 binding in IRAK-4. a) the binding mode of 1 in the ATP-binding pocket of IRAK-4 (PDB code: 2NRU). b) 1 superimposed on the AMP-PNP complex structure of IRAK-4 (PDB code: 2OID).

Fig. (9)

Initial thiazole amide IRAK-4 inhibitor and its pyridine amide analogue.

Fig. (10)

Cocrystal structures of aminopyrimidines in JNK-3. a) A more potent IRAK-4 compound: binding mode of 13 in JNK-3 (PDB code: 3CGF). b) A more potent JNK-3 compound: binding mode of 14 in JNK-3 (PDB code: 3CGO).

Fig. (11)

Lead compounds of the imidazo[1,2-a]pyridino-pyridine and benzimidazole pyridine series.

Fig. (12)

Imidazo[1,2-b]pyridazine and indazole IRAK-4 inhibitors.