PRT062607 [4-(3-(2H-1,2,3-triazol-2-yl)phenylamino)-2-((1R,2S)-2-aminocyclohexylamino)
pyrimidine-5-carboxamide] is a novel, highly specific, and potent
orally available small-molecule inhibitor of Spleen Tyrosine Kinase (Syk). The
potency of PRT062607 against its target kinase Syk was initially tested in two
different purified kinase assays. Using a FRET assay, half-maximal Syk
inhibition (IC50) required 6 ± 0.2 nM. Similar potency was observed
when tested in a radioactive enzyme assay, with a resulting Syk IC50
of 2.1 ± 0.4 nM [1].
The specificity of PRT062607 was tested in a panel of 270
independent purified kinase assays at 300 nM.
At this concentration, Syk and 8 other kinases (Fgr, MLK1, Yes, Flt3,
PAK5, Lyn, Src, Lck) were inhibited by greater than 80%. Subsequent analysis demonstrated a Syk IC50
of 1 nM, whereas the next most potently inhibited kinase, Fgr required an IC50
of 81 nM. PRT062607 also showed substantially weaker inhibitory potency against
the three kinases most homologous to Syk; namely, focal adhesion kinase (FAK),
protein tyrosine kinase 2 (PTK2), and Zap70 (IC50 = 415, 108 and
1050 nM, respectively) [2, 3]. In a variety of
cellular assays researchers observed potent inhibition of B cell receptor (BCR)
induced Syk signaling, but not of Lyn, phorbol 12-myristate 13-acetate (PMA)
induced protein kinase C, T cell receptor induced Zap70, or cytokine induced
JAK1 (IL6), JAK2 (GM-CSF), or JAK1/3 (IL4) dependent STAT phosphorylation. Consistently, in Ba/F3 cell lines transformed
by various kinases, PRT062607 only inhibited proliferation of those cells
transformed by Syk (IC50 = 0.12 µM), and not by Zap70 or JAK family
members (IC50 greater than 6 µM).
In human whole blood, PRT062607 suppressed BCR-induced Syk signaling and
cellular activation with IC50’s of 0.383 µM and 0.362 µM,
respectively. FceR1-induced basophil degranulation was similarly suppressed
with an IC50 of 0.171 µM [3].
On Oct 27, 2011 Biogen Idec and Portola Pharmaceuticals entered
into a licensing agreement to develop and commercialize PRT062607, for the
treatment of rheumatoid arthritis as well as other autoimmune and inflammatory
diseases. Biogen Idec will lead the global programme in major indications such
as rheumatoid arthritis, whereas Portola will lead development and
commercialization efforts in the United States for smaller indications, as well
as discovery efforts for follow-on SYK inhibitors. Portola retains an option to
co-promote alongside Biogen Idec in the United States in major indications.
Worldwide costs and profits will be split by Biogen and Portola 75 percent and
25 percent, respectively.
The activity of PRT062607 is as follows:
IC50 (SYK
enzyme assay, FRET assay) = 6 ± 0.2 nM
IC50 (SYK enzyme assay, Radioactive
enzyme assay) = 2.1 ± 0.4 nM; 1 nM
IC50 (FGR enzyme assay) = 81 nM
IC50 (MLK1 enzyme assay) = 88 nM
IC50 (YES enzyme assay) = 123 nM
IC50 (FLT3 enzyme assay) = 139 nM
IC50 (PAK5 enzyme assay) = 166 nM
IC50 (Lyn enzyme assay) = 192 nM
IC50 (c-Src enzyme assay) = 244 nM
IC50 (LCK enzyme assay) = 249 nM
Common Name: PRT062607
Synonyms: PRT-062607; PRT 062607; PRT062607; P505-15, BIIB057
IUPAC Name: 4-(3-(2H-1,2,3-triazol-2-yl)phenylamino)-2-((1R,2S)-2-aminocyclohexylamino)pyrimidine-5-carboxamide
CAS Number: 1370261-96-3; 1370261-97-4 (hydrochloride);
1370261-98-5 (acetate)
SMILES:NC(C(C=NC(N[C@@H]1CCCC[C@@H]1N)=N2)=C2NC3=CC(N4N=CC=N4)=CC=C3)=O
Mechanism of Action: Kinase Inhibitor; SYK Inhibitor
Indication: Anti-inflammatory Agents; Treatment of Rheumatoid arthritis;
Various Cancers
Development Stage: Phase I /II
Company: Portola Pharmaceuticals/Biogen Idec
Spleen tyrosine kinase (Syk) is broadly involved in regulating leukocyte immune function, principally by facilitating cellular activation in response to receptor engagement of antigen or immune complex. Receptors that use Syk for signal transduction include the B cell antigen receptor (BCR), Fc receptors, integrins, and members of the lectin and selectin families. Each of these Syk-dependent functions in various cell types is likely to be important in the etiology of inflammatory and autoimmune diseases. Syk is therefore considered an important target for controlling diseases involving immune cells. Recent evidence suggests that B-cell malignancies including non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL) can be driven by aberrant activity of cellular signaling pathways and by extrinsic factors from the microenvironment that interact with the BCR. Increased SYK expression and/or activity has been implicated in a number of NHL histologies [1,2].
Spleen tyrosine kinase (Syk) is broadly involved in regulating leukocyte immune function, principally by facilitating cellular activation in response to receptor engagement of antigen or immune complex. Receptors that use Syk for signal transduction include the B cell antigen receptor (BCR), Fc receptors, integrins, and members of the lectin and selectin families. Each of these Syk-dependent functions in various cell types is likely to be important in the etiology of inflammatory and autoimmune diseases. Syk is therefore considered an important target for controlling diseases involving immune cells. Recent evidence suggests that B-cell malignancies including non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL) can be driven by aberrant activity of cellular signaling pathways and by extrinsic factors from the microenvironment that interact with the BCR. Increased SYK expression and/or activity has been implicated in a number of NHL histologies [1,2].
Oral administration of PRT062607 in mice led to
a reversible inhibition of Syk, with an IC50 of 0.282 µM as
determined by an ex vivo whole blood BCR stimulation assay. Moreover, PRT062607 was tested for its immunomodulatory
potential of specific Syk inhibition in
vivo using rodent models of rheumatoid arthritis. Oral administration of PRT062607
resulted in statistically significant and dose-dependent anti-inflammatory
activity in both the mouse collagen antibody-induced arthritis and rat collagen
induced arthritis models. In each case,
anti-inflammatory effects were achieved at sub-micromolar plasma concentrations
in which Syk specificity was maintained [3].
With Fostamatinib (R788) bowing out of the race against rheumatoid
arthritis due to its promiscuous nature for other kinase targets along with
Syk, the hopes are now on PRT062607. PRT062607
is claimed to be more selective than Fostamatinib with direct support for Syk
as a target, whereas for Fostamatinib it was not certain whether efficacy and
toxicity were coming primarily from Syk inhibition. However, a planned phase II trial in rheumatoid arthritis was withdrawn prior to patient enrollment [4].
References:
1. Coffey, G.; et. al. Specific inhibition of spleen tyrosine kinase suppresses leukocyte immune function and inflammation in animal models of rheumatoid arthritis. J Pharmacol Exp Ther 2012, 340(2), 350-359.
2. Spurgeon, S. E.; et. al. The selective SYK inhibitor P505-15 (PRT062607) inhibits B cell signaling and function in vitro and in vivo and augments the activity of fludarabine in chronic lymphocytic leukemia. J Pharmacol Exp Ther 2013, 344(2), 378-387.
3. Coffey, G.; et. al. 1727 Specific Inhibition of Syk Suppresses Leukocyte Immune Function and Alleviates Inflammation In Rodent Models of Rheumatoid Arthritis. 53rd ASH Annual Meeting and Exposition, Dec 10-13, 2011.
4. ClinicalTrials.gov BIIB057 in Subjects With Rheumatoid Arthritis and Inadequate Response to Disease-Modifying Antirheumatic Drugs (EMBRACE). NCT01652937 (retrieved 01-Oct-2015)
4. ClinicalTrials.gov BIIB057 in Subjects With Rheumatoid Arthritis and Inadequate Response to Disease-Modifying Antirheumatic Drugs (EMBRACE). NCT01652937 (retrieved 01-Oct-2015)
