May 26, 2011 London, UK #THU0254
MPI-0485520, A SMALL MOLECULE INHIBITOR OF IKKE/TBK1 IS ACTIVE IN A MOUSE COLLAGEN-INDUCED ARTHRITIS MODEL
B. Richards 1, V. Baichwal 1, M. Cronin 1, L. Reeves 1, D. Papac 1, A. Yungai 1, P. Sebahar 1, R. Holcomb 1, D. Wettstein 1, P. Bartel 1,*, R. Carlson 1
1MYREXIS, Salt Lake City, United States
Background: Activation of the innate immune system has been proposed as a potential trigger for chronic inflammation associated with rheumatoid arthritis (RA). The innate immune system is activated within fibroblast-like synoviocytes via Toll-like receptors (TLRs) leading to secretion of proinflammatory chemokines that promote recruitment of inflammatory cells to the joint. The IKK-related kinases IKKε and TBK1 are essential in propagating TLR activation to IRF3 and IRF7 transcription factors. Phosphorylation of IRF3/7 leads to increased production of proinflammatory factors (IFN-β, RANTES, IP-10, MIP-1α, and IL-6) and proteinases (MMP-3 and MMP-9) and several of these proteins have been previously shown to be overexpressed in synoviocytes from RA patients.
Objectives: To determine if the potent and selective IKKε/TBK1 inhibitor MPI-0485520 reduces collagen-induced arthritis (CIA) in mice.
Methods: MPI-0485520 in vitro activity was assayed using recombinant IKKε and TBK1 enzymes. Production of the TLR3-induced cytokines, RANTES, IFN-β, IP-10, and MIP-1α, by fibroblast-like synoviocyte cells was measured by ELISA. In vivo efficacy of MPI-0485520 was determined in a mouse model of collagen-induced arthritis. Clinical arthritis score, weight, anti-collagen IgG titers and joint histology were evaluated in diseased mice.
Results: MPI-0485520 potently inhibits IKKε and TBK1 activities in vitro with IC50 values < 1 nM and reduces TLR3-induced RANTES, IFN-β, IP-10, and MIP-1α production in cultured fibroblast-like synoviocytes with IC50 values of 61, 12, 48 and 35 nM, respectively. MPI-0485520 also demonstrated efficacy in a collagen-induced arthritis model. Mice dosed for 16 days with either 100 or 150 mg/kg MPI-0485520 showed significant, dose-dependent reduction (p < 0.05) of 29% and 45%, respectively, in cumulative clinical arthritis score (number of joints affected, degree of erythema, and amount of swelling). The 100 and 150 mg/kg doses were well tolerated and resulted in 23% and 42% lower weight loss (p < 0.05), respectively, than vehicle-treated, collagen-immunized mice. Measurement of paw and joint histology showed a significant reduction (p < 0.05) of 37% in inflammation, pannus formation, cartilage loss, and bone destruction at the 150 mg/kg dose. The titer of arthritis-inducing anti-collagen antibodies was not modulated by MPI-0485520.
Conclusions: To our knowledge, this is the first example of an IKKε/TBK1 small molecule inhibitor demonstrating activity in a mouse model of arthritis. These results are consistent with IKKε-knockout mouse studies which demonstrated a role for IKKε in the progression of induced arthritis. Based on these observations, we anticipate that an orally available drug targeting the IKKε/TBK1 kinases may benefit patients suffering from rheumatoid arthritis.
MPI-0485520, A SMALL MOLECULE INHIBITOR OF IKKE/TBK1 IS ACTIVE IN A MOUSE COLLAGEN-INDUCED ARTHRITIS MODEL
B. Richards 1, V. Baichwal 1, M. Cronin 1, L. Reeves 1, D. Papac 1, A. Yungai 1, P. Sebahar 1, R. Holcomb 1, D. Wettstein 1, P. Bartel 1,*, R. Carlson 1
1MYREXIS, Salt Lake City, United States
Background: Activation of the innate immune system has been proposed as a potential trigger for chronic inflammation associated with rheumatoid arthritis (RA). The innate immune system is activated within fibroblast-like synoviocytes via Toll-like receptors (TLRs) leading to secretion of proinflammatory chemokines that promote recruitment of inflammatory cells to the joint. The IKK-related kinases IKKε and TBK1 are essential in propagating TLR activation to IRF3 and IRF7 transcription factors. Phosphorylation of IRF3/7 leads to increased production of proinflammatory factors (IFN-β, RANTES, IP-10, MIP-1α, and IL-6) and proteinases (MMP-3 and MMP-9) and several of these proteins have been previously shown to be overexpressed in synoviocytes from RA patients.
Objectives: To determine if the potent and selective IKKε/TBK1 inhibitor MPI-0485520 reduces collagen-induced arthritis (CIA) in mice.
Methods: MPI-0485520 in vitro activity was assayed using recombinant IKKε and TBK1 enzymes. Production of the TLR3-induced cytokines, RANTES, IFN-β, IP-10, and MIP-1α, by fibroblast-like synoviocyte cells was measured by ELISA. In vivo efficacy of MPI-0485520 was determined in a mouse model of collagen-induced arthritis. Clinical arthritis score, weight, anti-collagen IgG titers and joint histology were evaluated in diseased mice.
Results: MPI-0485520 potently inhibits IKKε and TBK1 activities in vitro with IC50 values < 1 nM and reduces TLR3-induced RANTES, IFN-β, IP-10, and MIP-1α production in cultured fibroblast-like synoviocytes with IC50 values of 61, 12, 48 and 35 nM, respectively. MPI-0485520 also demonstrated efficacy in a collagen-induced arthritis model. Mice dosed for 16 days with either 100 or 150 mg/kg MPI-0485520 showed significant, dose-dependent reduction (p < 0.05) of 29% and 45%, respectively, in cumulative clinical arthritis score (number of joints affected, degree of erythema, and amount of swelling). The 100 and 150 mg/kg doses were well tolerated and resulted in 23% and 42% lower weight loss (p < 0.05), respectively, than vehicle-treated, collagen-immunized mice. Measurement of paw and joint histology showed a significant reduction (p < 0.05) of 37% in inflammation, pannus formation, cartilage loss, and bone destruction at the 150 mg/kg dose. The titer of arthritis-inducing anti-collagen antibodies was not modulated by MPI-0485520.
Conclusions: To our knowledge, this is the first example of an IKKε/TBK1 small molecule inhibitor demonstrating activity in a mouse model of arthritis. These results are consistent with IKKε-knockout mouse studies which demonstrated a role for IKKε in the progression of induced arthritis. Based on these observations, we anticipate that an orally available drug targeting the IKKε/TBK1 kinases may benefit patients suffering from rheumatoid arthritis.
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