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A Dual Inhibition, a Better Solution: Development of a JAK1/TYK2 inhibitor Christel J Menet* Drug Discovery, Confo Therapeutics, Technologiepark 4, Ghent (Zwijnaarde) 9052, Belgium
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PF04965842 (5) or TYK2 inhibitors, BMS-986165, are currently in clinical development for autoimmune diseases such as RA, psoriasis, or Crohn’s disease.6,7 In this issue of the Journal of Medicinal Chemistry, Fensome et al.8 describe the evolution of a series of dual JAK1/TYK2 inhibitors from hit to the selection of PF-06700841 (6) as a clinical candidate. 6 is currently in development for the potential treatment of inflammatory diseases, including inflammatory bowel disease (IBD), alopecia areata, and psoriasis. Of particular interest in the article is the rationale for selecting 6 as a preclinical development candidate, nicely illustrating the complexities often encountered by drug discovery teams in translating in vitro pharmacology and SAR to in vivo studies. The sustained inhibition of the primary target in vivo is essential to understand the efficacy of the drug, as well as the level of inhibition of other targets to understand its safety margin. In JAK biology, in vitro biochemical assays using recombinant enzyme preparations have often misled medicinal chemists and have failed to capture the cell-based kinase inhibition of small molecules. In the cellular context, these inhibitors seems to be submitted to extra factors, such as local ATP concentrations or influence of the JAKs in the heterodimer linked to the cytokine receptor.9−11 Thus, the medicinal chemistry optimization, described by the Pfizer team in this article, is first done using the biochemical potencies obtained in the presence of 1 mM ATP (as 1 mM ATP is more representative of the cell physiology) and the final compound selection is driven by human whole blood assays for which the potencies are translated to the average concentration needed in an in vivo context. Given their tremendous experience in the JAK field and the high amount of data gathered on tafacitinib, the team made the observation that the efficacy was best explained by looking into the 24 h average drug concentration (Cav) and not, like often applied in drug discovery, by the Cmax or Cmin values.8 Accordingly, they translated the clinical PK:PD relationship into in vitro human whole blood cytokine inhibition, developing in vitro/in vivo correlations for their compounds. The efficacy is driven by the Cav IC80 of the primary targets TYK2 and JAK1, using the IFNα pathway, while the safety margin on the other hand is defined by Cav < IC30 of JAK2, using the EPO pathway (CD34+ cells spiked into human whole blood (HWB)). Therefore, to translate their obtained SAR, they calculated an ICxx* value (ICxx* = 100 × ((IC80 IFNα)/(IC80 IFNα + IC50 EPO)) to determine the predicted in vivo selectivity for EPO inhibition as a function of the IFNα HWB IC80.
ver the past 2 decades, there has been a rapid development of novel therapies for the treatment of autoimmune diseases, with an impressive success in biologics. Inhibiting different cytokine pathways can tackle different conditions and has proven to have great efficacy. For example, anti-IL12/IL23 or more selective anti-IL23 treatments have been approved to treat psoriasis and psoriatic arthritis and are now also approved in Europe and the U.S. to treat patients with Crohn’s disease. They show a clear efficacy with a good safety profile.1 However, despite these therapeutic developments, immunogenicity will continue to be a downside of therapeutic antibodies, on top of the fact that currently they are only given via parenteral administration. Janus kinase [JAK] inhibitors are small molecules that are marketed or currently under development for the treatment of several immune diseases including psoriasis, rheumatoid arthritis (RA), and IBD.2 The JAK family members are tyrosine kinases and composed of four members: JAK1, JAK2, JAK3, and TYK2. They associate with the intracellular domain of a wide range of cytokines and some growth factor receptor chains. JAKs get activated through ligand-induced conformational changes of receptor complexes and as such initiate a phosphorylation cascade that leads to the activation of members of the signal transducer and activator of transcription (STAT) family.3 Phosphorylated STATs then translocate to the nucleus and reprogram gene expression in a liganddependent manner (Figure 1). It has been demonstrated that different cytokine receptors are associated with a specific heterodimer or homodimer of JAK enzymes (Figure 2) and that each JAK is linked to more than one receptor. Numerous studies in the literature has shown that JAK1/JAK3 depends on γ-common chain cytokines, the JAK1/JAK2 complex is associated with INFγ, IL-6 and other gp130 cytokines, while the JAK1/TYK2 heterodimer binds to type I interferons and the IL-10 family of cytokines. JAK2 is the only one forming a homodimer on EPO and leptin receptor. A number of JAK inhibitors have reached the market or are still in clinical development. These inhibitors harbor different profiles. Jakafi (1, Chart 1), the first JAK inhibitor reaching the market, is a JAK1/JAK2 inhibitor used for the treatment of polycythemia vera or myelofibrosis.4 Tofacitinib (2), the first JAK used to tackle autoimmune diseases, is a PAN JAK inhibitor, with some selectivity toward JAK1, JAK2, and JAK3.5 With all the acquired knowledge on the JAKs and their involvement on the cytokine receptors, pharmaceutical companies in the past 10 years have been trying to develop compounds with better selectivity profiles, consequently able to modulate the different cytokine signaling pathways. Some JAK1 inhibitors such as filgotinib (3), upadacitinib (4), and © 2018 American Chemical Society
Received: September 7, 2018 Published: September 25, 2018 8594
DOI: 10.1021/acs.jmedchem.8b01397 J. Med. Chem. 2018, 61, 8594−8596
Journal of Medicinal Chemistry
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Figure 1. Cytokine signaling.
Figure 2. JAK kinases are linked to cytokine receptors as Heterodimers.
Chart 1
nM (in the CD3+ cellular subset), and lower inhibition of IL6/ pSTAT3 (IC50) = 641 nM in the CD3+ cellular subset. Interestingly, despite the relatively common kinase scaffold aminopyrimidine, 6 exhibits excellent kinase selectivity. Selectivity was evaluated on 157 kinases in the presence of 1 mM ATP, wherein only the JAKs and TNK1 (64%) show an inhibition higher than 50%. Inhibitor 6 was also profiled in vitro against a broad panel of receptors, ion channels, and transporters in the CEREP wide ligand profile screen at a single concentration of 10 μM which again confirmed its great selectivity. Furthermore, its low aqueous solubility was anticipated by preparing a salt form of 6 which showed improved solubility in gastric fluids (>7 mg/mL) (FESSIF, FASSIF). The relatively low clearance in in vitro microsomal and hepatotocyte metabolism and the high passive permeability (>18.8 × 10−6 cm/s) rationalize the good bioavailability. Sprague-Dawley rats, following intravenous and oral administration (1 mg/kg and 3 mg/kg, respectively) of the tosylate salt, showed a plasma clearance of 31 mL min−1 kg−1, a volume of
In their design and the testing of their compounds, the authors illustrate some notable medicinal chemistry design themes. First, the use of structure-based drug discovery drives the potency and selectivity of their molecules through a clear understanding of the difference between each JAK isoform and the role of each residue involved in the established binding. Second, the incorporation of polarity into small molecule inhibitors or removal of structural alerts such as anilines proved to be of paramount value for compound prioritization. Among the described analogs, 6 exhibited the best pharmacological profile. 6 is a potent dual inhibitor of JAK1 and TYK2 (IC50(JAK1) = 17 nM; IC50(TYK2) = 23 nM) with some selectivity against JAK2 (IC50 = 77 nM) and JAK3 (IC50 = 6494 nM). Notably, the translation from biochemical to cellbased activity in whole blood shows a great selectivity of the compound with INFα HWB = 30 nM and EPO ICxx* = 18. Further profiling in human whole blood assays on different cytokine signaling pathways confirmed the selectivity of the compound, with IL-12/pSTAT4 HWB (IC50) = 65 nM, IL23/pSTAT3 HWB (IC50) = 120 nM, IL6/pStat1 (IC50) = 81 8595
DOI: 10.1021/acs.jmedchem.8b01397 J. Med. Chem. 2018, 61, 8594−8596
Journal of Medicinal Chemistry
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(10) Sohn, S. J.; Barrett, K.; Van Abbema, A.; Chang, C.; Bir Kohli, P.; Kanda, H.; Smith, J.; Lai, Y.; Zhou, A.; Zhang, B.; Yang, W.; Williams, K.; Macleod, C.; Hurley, C. A.; Kulagowski, J. J.; LewinKoh, N.; Dengler, H. S.; Johnson, A. R.; Ghilardi, N.; Zak, M.; Liang, J.; Blair, W. S.; Magnuson, S.; Wu, L. C. A Restricted Role for TYK2 Catalytic Activity in Human Cytokine Responses Revealed by Novel TYK2-Selective Inhibitors. J. Immunol. 2013, 191 (5), 2205−2216. (11) Thorarensen, A.; Banker, M. E.; Fensome, A.; Telliez, J. P.; Juba, B.; Vincent, F.; Czerwinski, R. M.; Casimiro-Garcia, A. ATPmediated kinome selectivity: The missing link in understanding the contribution of individual JAK kinase isoforms to cellular signaling. ACS Chem. Biol. 2014, 9 (7), 1552−1558. (12) Banfield, C.; Scaramozza, M.; Zhang, W.; Kieras, E.; Page, K. M.; Fensome, A.; Vincent, M.; Dowty, M. E.; Goteti, K.; Winkle, P. J.; Peeva, E. The Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of a TYK2/JAK1 Inhibitor (PF-06700841) in Healthy Subjects and Patients With Plaque Psoriasis. J. Clin. Pharmacol. 2018, 58 (4), 434−447.
distribution of 2.0 L/kg, and an oral bioavailability of 83%. Upon administration of the 3 mg/kg oral dose, the measured Cmax was 774 ng/mL and the AUC∞ was 1340 ng·h/mL. Finally, the success of the approach was demonstrated by curative treatment of rat adjuvant induced arthritis (AIA) following oral dosing in a dose-dependent study, with concomitant time-dependent plasma exposure. In summary, 6 represents a promising addition to the armory of JAK enzyme inhibitors for clinical evaluation. Its selectivity profile, together with its good oral bioavailability, allows definitive testing of the clinical hypothesis that a dual inhibition of JAK1 and TYK2 can lead to a clinical benefit at a well-tolerated dosing regimen. In a more recent paper,12 the phase 1 study results indicate that the TYK2/JAK1 inhibitor 6 has a favorable safety profile and is well tolerated at single doses up to 200 mg and multiple doses up to 175 mg once daily in healthy subjects and up to 100 mg once daily in patients with plaque psoriasis, respectively. The obtained results suggest that treatment with 6 leads to a clinical benefit as measured by PASI scores in patients with plaque psoriasis, supporting further clinical development of 6 in the treatment of psoriasis and other inflammatory diseases.
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REFERENCES
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DOI: 10.1021/acs.jmedchem.8b01397 J. Med. Chem. 2018, 61, 8594−8596
