Christel Jeanne Marie Menet

Preclinical Characterization of GLPG0634, a Selective Inhibitor of JAK1, for the Treatment of Inflammatory Diseases

The JAKs receive continued interest as therapeutic targets for autoimmune, inflammatory, and oncological diseases. JAKs play critical roles in the development and biology of the hematopoietic system, as evidenced by mouse and human genetics. JAK1 is critical for the signal transduction of many type I and type II inflammatory cytokine receptors. In a search for JAK small molecule inhibitors, GLPG0634 was identified as a lead compound belonging to a novel class of JAK inhibitors. It displayed a JAK1/JAK2 inhibitor profile in biochemical assays, but subsequent studies in cellular and whole blood assays revealed a selectivity of ∼30-fold for JAK1- over JAK2-dependent signaling. GLPG0634 dose-dependently inhibited Th1 and Th2 differentiation and to a lesser extent the differentiation of Th17 cells in vitro. GLPG0634 was well exposed in rodents upon oral dosing, and exposure levels correlated with repression of Mx2 expression in leukocytes. Oral dosing of GLPG0634 in a therapeutic set-up in a collagen-induced arthritis model in rodents resulted in a significant dose-dependent reduction of the disease progression. Paw swelling, bone and cartilage degradation, and levels of inflammatory cytokines were reduced by GLPG0634 treatment. Efficacy of GLPG0634 in the collagen-induced arthritis models was comparable to the results obtained with etanercept. In conclusion, the JAK1 selective inhibitor GLPG0634 is a promising novel therapeutic with potential for oral treatment of rheumatoid arthritis and possibly other immune-inflammatory diseases.

Type II Kinase Inhibitors: An Opportunity in Cancer for Rational Design

With the advent of the Type II kinase inhibitor imatinib (Gleevec) for treatment against cancer, rational design of tailored molecules has brought a revolution in medicinal chemistry for treating tumours caused by kinase malfunctioning. Among different types of kinase inhibitors, the design of Type II inhibitors has been rationalized for maximizing the benefits and reducing drawbacks. Here we highlight the development made in Type II inhibitors, discussing the advantages and disadvantages of these types of molecules. Furthermore, we present the strategies for designing druggable molecules that either selectively inhibit target kinases or overcome drug resistance.

Advances in the Discovery of Selective JAK Inhibitors

In this review, we describe the current knowledge of the biology of the JAKs. The JAK family comprises the four nonreceptor tyrosine kinases JAK1, JAK2, JAK3, and Tyk2, all key players in the signal transduction from cytokine receptors to transcription factor activation. We also review the progresses made towards the optimization of JAK inhibitors and the importance of their selectivity profile. Indeed, the full array of many medicinal chemistry enabling tools (HTS, X-ray crystallography, scaffold morphing, etc.) has been deployed to successfully design molecules that discriminate among JAK family and other kinases. While the first JAK inhibitor was launched in 2011, this review also summarizes the status of several other small-molecule JAK inhibitors currently in development to treat arthritis, psoriasis, organ rejection, and multiple cancer types.

Triazolopyridines as Selective JAK1 Inhibitors: From Hit Identification to GLPG0634

Janus kinases (JAK1, JAK2, JAK3, and TYK2) are involved in the signaling of multiple cytokines important in cellular function. Blockade of the JAK-STAT pathway with a small molecule has been shown to provide therapeutic immunomodulation. Having identified JAK1 as a possible new target for arthritis at Galapagos, the compound library was screened against JAK1, resulting in the identification of a triazolopyridine-based series of inhibitors represented by 3. Optimization within this chemical series led to identification of GLPG0634 (65, filgotinib), a selective JAK1 inhibitor currently in phase 2B development for RA and phase 2A development for Crohns disease (CD).

Progress toward JAK1-selective inhibitors.

The discovery of the JAK-STAT pathway was a landmark in cell biology. The identification of these pathways has changed the landscape of treatment of rheumatoid arthritis and other autoimmune diseases. The two first (unselective) JAK inhibitors have recently been approved by the US FDA for the treatment of myelofibrosis and rheumatoid arthritis and many other JAK inhibitors are currently in clinical development or at the discovery stage. Research groups have demonstrated the different roles of JAK member and the therapeutic potential of targeting them selectively. JAK1 plays a critical and potentially dominant role in the transduction of γc cytokine (γc = common γ chain) and in IL-6 signaling. In this review, we will discuss the state-of-the-art research that evokes JAK1 selective inhibition.

THU0138 Glpg0634m1, A Major Metabolite of the Jak1-Selective Inhibitor Glpg0634, is Also Jak1-Selective and Efficient in the Rat CIA Model

Background GLPG0634 is a JAK inhibitor displaying a high selectivity for JAK1 over JAK2 in human whole blood assays. It is currently being developed as an oral treatment for rheumatoid arthritis (RA) and showed good efficacy and tolerability in two 4-week Phase 2a RA studies. GLPG0634 has a major metabolite, GLPG0634m1, with a half-life which might contribute to its clinical efficacy in RA patients. Objectives Characterize the pharmacological properties of the GLPG0634m1, its activity on JAK-driven pathways and its efficacy in the rat CIA (collagen-induced arthritis) model. Methods Selectivity of the metabolite GLPG0634m1 was measured in vitro in radiometric recombinant kinase assays and ex vivo in whole blood assays (human, dog and monkey) by monitoring STAT phosphorylation by flow cytometry. Rats with established arthritis were treated with the GLPG0634m1 molecule (60 mg/kg po, QD) or etanercept (10 mg/kg ip, 3 times a week). The clinical score as well as histological parameters were used to monitor/quantify disease progression. Plasma concentration of the molecule was quantified by LC-MS/MS. Results Biochemical analysis of potency of GLPG0634m1 on recombinant JAK kinases showed that this compound is 10-fold less active against JAK1 and JAK2 than GLPG0634 with IC50s of 546 nM and 624 nM, respectively. Potency on JAK3 and TYK2 over 3 μM indicates that this molecule is more selective for JAK1 and JAK2 compared to JAK3 and TYK2. In human whole blood assays (WBA), GLPG0634m1 inhibited a JAK1-dependent event (IL-6-induced STAT1 phosphorylation) with an IC50 of 11.9 μM and a JAK2-dependent event (GMCSF-induced STAT5 phosphorylation) with an IC50 exceeding 100 μM, revealing the >10-fold selectivity of this molecule for JAK1 over JAK2. The JAK1 potency was confirmed with assays using IL2-induced STAT5 and IFNα-induced STAT1 phosphorylation, respectively triggering the JAK1/JAK3 and JAK1/TYK2 pathways. When given orally to rats with established arthritis, GLPG0634m1 displayed a pronounced efficacy comparable to etanercept, strongly reducing the impact of disease on e.g. paw swelling and Larsen score. These effects were confirmed at histological level with decreased pannus severity, bone and cartilage lesion as well as cell infiltration indexes. Plasma levels of GLPG0634m1 exceeded its WBA-derived JAK1 IC50 but were far below its WBA-derived JAK2 IC50, implying that the metabolite efficacy in the CIA model is driven by JAK1 inhibition, as observed previously with the parent molecule. Conclusions While displaying a lower potency compared to its parent molecule, GLPG0634m1 has a similar JAK1 selectivity. Oral administration of this metabolite, albeit at a 10-times higher dose than GLPG0634, reduces inflammation in the rat CIA model to the same extent as parenteral etanercept, an effect that is supported by JAK1 inhibition but appears independent of JAK2 inhibition. These findings, together with the high exposure and long half-life of this metabolite observed in phase 1 and phase 2 clinical studies in humans, strongly suggest that it may contribute to the clinical efficacy of the parent compound GLPG0634 in RA. Disclosure of Interest : C. Belleville-Da-Costa Grant/research support: Abbvie, Employee of: Galapagos SASU, D. Merciris Grant/research support: Abbvie, Employee of: Galapagos SASU, B. Vayssière Grant/research support: Abbvie, Employee of: Galapagos SASU, N. Houvenaghel Grant/research support: Abbvie, Employee of: Galapagos NV, A. Monjardet Grant/research support: Abbvie, Employee of: Galapagos SASU, L. Lepescheux Grant/research support: Abbvie, Employee of: Galapagos SASU, S. Dupont Grant/research support: Abbvie, Employee of: Galapagos SASU, T. Christophe Grant/research support: Abbvie, Employee of: Galapagos NV, M. Borgonovi Grant/research support: Abbvie, Employee of: Galapagos SASU, P. Clément-Lacroix Grant/research support: Abbvie, Employee of: Galapagos SASU, C. Menet Grant/research support: Abbvie, Employee of: Galapagos NV, L. Van Rompaey Grant/research support: Abbvie, Employee of: Galapagos NV, R. Brys Grant/research support: Abbvie, Employee of: Galapagos NV, R. Galien Grant/research support: Abbvie, Employee of: Galapagos SASU DOI 10.1136/annrheumdis-2014-eular.4291