Bioorg. Med. Chem. Lett. 2015 Oct 15;25(20):4441-6.

Highly potent and selective pyrazolylpyrimidines as Syk kinase inhibitors


Jang-Sik Choia,b, Hae-jun Hwangb, Se-Won Kimb, Byung Il Leec, Jaekyoo Leed, Ho-Juhn Songd, Jong Sung Kohd, Jung-Ho Kimb,*, Phil Ho Leea,*

a Department of Chemistry, Kangwon National University, Chuncheon 200-701, Republic of Korea

b Oscotec Inc., 694-1 Sampyeong-dong, Bundang-gu, Seongnam-si, Gyeonggi-do 463-400, Republic of Korea

c Biomolecular Function Research Branch, Division of Convergence Technology, Research Institute, National Cancer Center, Goyang, Gyeonggi 410-769, Republic of Korea

d Genosco, 767C Concord Avenue, 2nd Floor, Cambridge, MA 02138, USA



A series of pyrazolylpyrimidine scaffold based Syk inhibitors were synthesized and evaluated for their biological activities and selectivity. Lead optimization efforts provided compounds with potent Syk inhibition in both enzymatic and TNF-α release assay.



SYK is an intracellular protein tyrosine kinase expressed in most of the hematopoietic cells and a crucial mediator in signal pathway (Figure 1) of Fc receptor and B cell receptor whose dysfunction readily leads to various immunological disorders such as rheumatoid arthritis (RA), systemic lupus erythromatosus (SLE), immune thrombocytopenic purpura (ITP), and even hematological malignance (1-3). For example, it was reported that highly phosphorylated SYK proteins were found in the RA patient’s synovium and further more SYK knockout mouse showed complete inhibition of all macroscopic and microscopic signs of RA after challenged with arthritic serum (4). Therefore, SYK is reasonable and promising therapeutic target for treatment of RA and other immune disorders.




Figure 1. Schematic drawing of SYK signal pathway.


fig2Figure 2. Establishment and dosing scheme of mouse CIA model.


Several SYK inhibitors have been clinically developed for the treatment of RA (5). Some of them showed partial improvement of RA symptom but failed to show desirable clinical outcomes partly due to severe adverse events. Adverse events are speculated to originate from strong inhibition of other kinases such as KDR and ZAP70, subsequently leading to adverse off-target effect. Therefore, there is an increasing demand to generate a highly selective and potent SYK inhibitor with desirable safety profiles for the treatment of therapeutic needs like RA and other immune disorders.

As a representative example of pyrazolylpyrimidines derivative as shown in this study, SKI-O-282 showed potent inhibitory effect on SYK (IC50 of 1.0 nM) in a cell-free assay and was highly selective to SYK in a panel of 298 kinases at 10 nM. SKI-O-282 effectively inhibited FcgR-, FceR- and BCR-mediated signaling pathways with IC50 ranging from 38 to 237 nM. SKI-O-282 showed potent efficacy in a collagen-induced arthritis mouse model (Figure 2, Figure 3).




Figure 3. Arthritic score of methotrexate (MTX), R788 and SKI-O-282 in mouse CIA model. Test articles and reference compounds were orally dosed once a day. SKI-O-282 of 30 mg/kg dose showed better efficacy than R788 (Fostamatinib) of 30 mg/kg dose and MTX of 1.5 mg/kg dose.



Figure 4. Potent inhibition of phosphorylated SYK in pulverized hind limb of CIA mouse.


Furthermore, 10 and 30 mg/kg dosing of SKI-O-282 significantly inhibited phosphorylated SYK (p-SYK) in pulverized hind limb of CIA mouse in dose dependent manner and corresponding inhibition of downstream effectors such as p-Vav and p-PLCg2 (Figure 4). The inhibitory level of p-SYK in hind limb is well correlated with pharmacological efficacy in the CIA model. Unfortunately its intrinsic chemical property showed cardiac toxicity in toxicology study so that it was not chosen as a lead candidate for IND enabling toxicology and safety study. However, from our rational design of pyrazolylpyrimidines derivative as shown in this study, we were finally able to generate orally bioavailible and highly selective SYK inhibitor, SKI-O-703 with both desirable potency and drug-like properties and desirable safety in GLP toxicology study, which is currently in phase I clinical trial to assess its safety and tolerability and aims to treat RA, SLE and ITP.



  1. Bajpai M, Chopra P, Dastidar SG, Ray A. 2008. Spleen tyrosine kinase: a novel target for therapeutic intervention of rheumatoid arthritis. Exp. Opin. Investig. Drugs 17: 641–659
  2. Grammatikos AP, Ghosh D, Devlin A, Kyttaris VC, Tsokos GC. 2013. Spleen Tyrosine Kinase (Syk) Regulates Systemic Lupus Erythematosus (SLE) T Cell Signaling. PLoS ONE 8: e74550
  3. Podolanczuk A, Lazarus AH, Crow AR, Grossbard E, Bussel JB. 2009. Of mice and men: an open-label pilot study for treatment of immune thrombocytopenic purpura by an inhibitor of Syk. Blood 113: 3154-3160
  4. Jakus Z, Simon E, Balazs B, Mocsai A. 2010. Genetic deficiency of Syk protects mice from autoantibody-induced arthritis. Arthritis Rheum. 62: 1899-1910
  5. Tam FWK, McAdoo SP. 2011. Fostamatinib disodium. Tyrosine-protein kinase SYK/FLT3 inhibitor, Treatment of rheumatoid arthritis, Oncolytic. Drugs Future 36: 273-280



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