In the past decade there has been considerable interest in targeting the innate immune system in the treatment of autoimmune diseases and sterile inflammation. Receptors of the innate immune system provide the first line of defense against bacterial and viral insults. These receptors recognize bacterial and viral products as well as pro-inflammatory cytokines and thereby initiate a signaling cascade that ultimately results in the up-regulation of inflammatory cytokines such as TNFα, IL6, and interferons. Recently it has become apparent that self-generated ligands such as nucleic acids and products of inflammation such as HMGB1 and Advanced Glycated End-products (AGE) are ligands for Toll-like receptors (TLRs) which are key receptors of the innate immune system.
This demonstrates the role of TLRs in the initiation and perpetuation of inflammation due to autoimmunity.
Interleukin-1 receptor associated kinase (IRAK4) is a ubiquitously expressed serine/threonine kinase involved in the regulation of innate immunity. IRAK4 is responsible for initiating signaling from TLRs and members of the IL-1/18 receptor family. Kinase-inactive knock-ins and targeted deletions of IRAK4 in mice lead to reductions in TLR and IL-1 induced pro-inflammatory cytokines. and 7 IRAK-4 kinase-dead knock-in mice have been shown to be resistant to induced joint inflammation in the antigen-induced-arthritis (AIA) and serum transfer-induced (K/BxN) arthritis models. Likewise, humans deficient in IRAK4 also display the inability to respond to challenge by TLR ligands and IL-1
However, the immunodeficient phenotype of IRAK4-null individuals is narrowly restricted to challenge by gram positive bacteria, but not gram negative bacteria, viruses or fungi. This gram positive sensitivity also lessens with age implying redundant or compensatory mechanisms for innate immunity in the absence of IRAK4.These data suggest that inhibitors of IRAK4 kinase activity will have therapeutic value in treating cytokine driven autoimmune diseases while having minimal immunosuppressive side effects. Additional recent studies suggest that targeting IRAK4 may be a viable strategy for the treatment of other inflammatory pathologies such as atherosclerosis.
Indeed, the therapeutic potential of IRAK4 inhibitors has been recognized by others within the drug-discovery community as evidenced by the variety of IRAK4 inhibitors have been reported to-date.12, 13, 14, 15 and 16 However, limited data has been published about these compounds and they appear to suffer from a variety of issues such as poor kinase selectivity and poor whole-blood potency that preclude their advancement into the pre-clinical models. To the best of our knowledge, no in vivo studies of IRAK4 inhibitors have been reported to-date in the literature. Herein we report a new class of IRAK4 inhibitors that are shown to recapitulate the phenotype observed in IRAK4 knockout and kinase-dead mice.
Bioorganic & Medicinal Chemistry Letters (2014), 24(9), 2066-2072.
Identification and optimization of indolo[2,3-c]quinoline inhibitors of IRAK4
- a Pfizer Global R&D, 445 Eastern Point Rd., Groton, CT 06340, USA
- b Pfizer Global R&D, 200 Cambridge Park Dr., Cambridge, MA 02140, USA
- c Pfizer Global R&D, 87 Cambridgepark Dr., Cambridge, MA 02140, USA
- d Pfizer Global R&D, 1 Burtt Rd., Andover, MA 01810, USA
IRAK4 is responsible for initiating signaling from Toll-like receptors (TLRs) and members of the IL-1/18 receptor family. Kinase-inactive knock-ins and targeted deletions of IRAK4 in mice cause reductions in TLR induced pro-inflammatory cytokines and these mice are resistant to various models of arthritis. Herein we report the identification and optimization of a series of potent IRAK4 inhibitors. Representative examples from this series showed excellent selectivity over a panel of kinases, including the kinases known to play a role in TLR-mediated signaling. The compounds exhibited low nM potency in LPS- and R848-induced cytokine assays indicating that they are blocking the TLR signaling pathway. A key compound (26) from this series was profiled in more detail and found to have an excellent pharmaceutical profile as measured by predictive assays such as microsomal stability, TPSA, solubility, and c log P. However, this compound was found to afford poor exposure in mouse upon IP or IV administration. We found that removal of the ionizable solubilizing group (32) led to increased exposure, presumably due to increased permeability. Compounds 26 and 32, when dosed to plasma levels corresponding to ex vivo whole blood potency, were shown to inhibit LPS-induced TNFα in an in vivo murine model. To our knowledge, this is the first published in vivo demonstration that inhibition of the IRAK4 pathway by a small molecule can recapitulate the phenotype of IRAK4 knockout mice.
////////PF-05387252, 1604034-71-0, PF 05387252, TLR signaling, Indoloquinoline, IRAK4, Kinase inhibitor, Inflammation, PRECLINICAL